Next Article in Journal
Efficacy of Cord Blood Cell Therapy for Hutchinson–Gilford Progeria Syndrome—A Case Report
Next Article in Special Issue
What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment
Previous Article in Journal
Chymase as a Novel Therapeutic Target in Acute Pancreatitis
Previous Article in Special Issue
What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 4: Experimental Treatments in Pre-Clinical Studies (Cell Lines and Mouse Models)
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1

by 1,*, 2, 1, 1, 3, 4,5, 6, 1, 1, 7, 8, 1, 9,10, 11,12, 13, 5,13, 14, 15, 15, 16, 16, 17, 18, 19, 19, 1,5 and 2add Show full author list remove Hide full author list
1
Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
2
Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
3
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy
4
Fertility Center, Department of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
5
Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy
6
Pathology Unit, Policlinico Riuniti, University of Foggia, 71122 Foggia, Italy
7
Department of Scientific Research, School of Postgraduate Studies, Norte University, Asunción 1614, Paraguay
8
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
9
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
10
Gastroenterology Division, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
11
Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy
12
Haematopathology Unit, CREO, Azienda Ospedaliera di Perugia, University of Perugia, 06129 Perugia, Italy
13
Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
14
Molecular Diagnostic Unit, Azienda USL Bologna, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy
15
Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
16
Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy
17
Barts Cancer Institute, Queen Mary University of London, London EC1M 5PZ, UK
18
Department of Pathology and Laboratory Medicine, University of Washington, Seattle, WA 98195, USA
19
Molecular Biology Laboratory, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(22), 12314; https://doi.org/10.3390/ijms222212314
Submission received: 12 August 2021 / Revised: 18 October 2021 / Accepted: 22 October 2021 / Published: 15 November 2021
(This article belongs to the Special Issue Biomarker-Oriented Treatment of Urogenital Cancers)

Abstract

:
Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the CD274 promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation.

1. Introduction

As the discovery of novel biomarkers is urgently required to develop tailored therapies for various malignancies [1], increasing attention has been paid to immunotherapy targets such as Programmed death-1 (PD-1) and its ligand (PD-L1). They are type I transmembrane glycoproteins transcribed by PDCD1 (located on chromosome 2) and CD274 genes (located on chromosome 9), respectively [2,3]. PD-1 is expressed by activated T, B, NK cells, and monocytes, while PD-L1 is found on hematopoietic and non-hematopoietic cells: their expression is inducible by microenvironmental conditions [2,3]. Indeed, pembrolizumab monotherapy (anti-PD-1 monoclonal antibody) recently revealed good therapeutic activity, and the 2021 United States National Comprehensive Cancer Network (NCCN) guidelines have considered this drug indicated in selected prostate cancer (PC) patients [4,5]. So, at least in the US, patients with metastatic castration-resistant PCs showing microsatellite instability/mismatch-repair protein system deficiency (MSI-H/dMMR) could be treated with pembrolizumab as a second-line therapy setting or beyond. Unfortunately, the prevalence of MSI-H/dMMR PCs is low, and the administration of immunotherapy in PC patients is still limited in the current clinical practice [4,5].
Epigenetic alterations induce reversible and heritable changes, promoting differences in the expressions of oncogenes and oncosuppressor genes without changing the DNA sequence [6]. DNA methylation, covalent histone modifications, histone variants, microRNAs (miRNAs) effects, and chromatin-remodeling complexes are well-identified epigenetic mechanisms. However, PC displays a complex genetic and epigenetic regulation, leading to changes in cell growth pathways and overall tumor progression [6].
Epigenetic modifications accumulated by cancer cells influence gene expression and may contribute to tumor immune escape, also by targeting checkpoint inhibitors such as PD-L1. Moreover, epigenetic modulating drugs may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion [7,8,9,10,11].
Unfortunately, despite the increasing attention on molecular and epigenetic regulators in PCs, there is still limited evidence concerning the complex network of epigenetic factors modulating PD-L1 expression in PC [12]. In our systematic literature review, we have tried to describe the current knowledge on this topic.

2. Results

2.1. Literature Review Results

Figure 1 presents the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) (http://www.prisma-statement.org/, accessed on 8 May 2021) flow chart, summarizing the research method and results of our systematic literature review.
We identified 263 articles on PubMed (Available online: https://pubmed.ncbi.nlm.nih.gov, accessed on 8 May 2021), 385 articles on Scopus (Available online: https://www.scopus.com/home.uri, accessed on 8 May 2021), and 399 articles on Web of Science databases (Available online: https://login.webofknowledge.com, accessed on 8 May 2021). After duplicates exclusion, 560 records underwent a screening of titles and abstracts. 155 articles were considered eligible, as they seemed to report clinic-pathologic studies on human patients or experimental research on pre-clinical models (tumor cell lines, mouse models, etc.) investigating the role of PD-L1 in PC. After reading the full texts of all these papers, 7 articles were excluded for being unfit according to the inclusion criteria or for presenting scant or aggregated data. 148 articles were finally included in our study [5,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159]. Further details are available in Section 4.

2.2. Epigenetic Regulation of PD-L1 Expression: Pre-Clinical Models

PD-L1 expression is under epigenetic control, as demonstrated by functional and correlation studies on PC cell lines (Table 1 and Table 2) [7,14,26,60,73,115,116,123,127,159].
In PC cell lines (Table 1), the methylation of CpG sequences in the CD274 (PD-L1) gene promoter by DNA methyltransferases (DNMTs) negatively regulated PD-L1 expression [7]. To inhibit PD-L1, Li et al. [7] used recombinant constructs expressing the C-terminal domains of DNMT3a and/or DNMT1 fused with a zinc finger domain specifically binding to the PD-L1 promoter (Ad-ZF-DNMT3aC-1C, Ad-ZF-DNMT3aC, Ad-ZF-DNMT1C). Human PC cell lines (DU145) treated with Ad-ZF-DNMT3aC-1C showed a significant reduction in PD-L1 expression when compared to Ad-ZF-DNMT3aC or Ad-ZF-DNMT1C alone [7].
Histone modifiers also influence the PD-L1 transcription rate in PC cell lines: data suggested that the deletion or silencing of the histone modifiers MLL3 and MML1 may positively regulate PD-L1 expression [14,60]. Xiong et al. [60] found that MLL3 bound to the PD-L1 enhancer, while MLL3 depletion decreased the binding of the methylated histone H3 on Lysine 4 in the PD-L1 enhancer and Pol II Ser5p in the PD-L1 promoter. Moreover, it impaired mouse xenograft growth, decreasing the response to the PD-L1 antibody treatment.
The transcription factor IRF-1 could recruit p300 to the CD274 promoter, inducing the acetylation of histone H3 and increasing CD274 transcription [116]. In PC cell lines, protein levels of the histone deacetylase HDAC1 negatively correlated to PD-L1 levels, while there was no correlation between HDAC2/3 and PD-L1 [116].
Functional studies (Table 2) revealed that treatments with epigenetic drugs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) [116,123,127] induced a reduction of PD-L1 expression; conversely, epigenetic drugs inducing a chromatin-active state (i.e., HDAC inhibitors) increased PD-L1 expression [116]. In an experimental study [116], p300 inhibitors (but not anti-PD-L1 antibodies) significantly enhanced the efficacy of HDAC inhibitors on limiting tumor progression by blocking the HDAC inhibition-induced PD-L1 expression.
Class I and II HDAC inhibitors such as SAHA (vorinostat) and LBH589 (panobinostat), as well as IFN-γ, significantly increased CD274 expression in PC cell lines. RNA polymerase II was also enriched at the CD274 promoter after HDAC treatment [116]. A485 may enhance the efficacy of treatments with anti-PD-L1 antibodies, decreasing the PD-L1 expression and reducing the exosomal PD-L1 secreted by PC cell lines; the combined administration of these drugs inhibited the androgen-independent metastatic tumor growth in syngeneic PC models [116].
The histone methylation regulator WDR5 (WD repeat-containing protein 5) was overexpressed in PCs with advanced clinic-pathological features and seemed important for PD-L1 transcription [14]. In PC cell lines, the IFN-γ-induced PD-L1 mRNA and protein levels were significantly abrogated by WDR5 or MLL1 knockdown (not by c-MYC silencing), as well as by OICR-9429 (a highly selected and potent antagonist of WDR5 interactions with MLL1, c-MYC, and other partners) [14]. Some cell cycle, anti-apoptosis, DNA repair, and immune-related genes (such as AURKA, CCNB1, E2F1, PLK1, BIRC5, XRCC2, and CD274) were directly regulated by WDR5 and OICR-9429 in a H3K4me3 (histone H3 Lysine 4 tri-methylation)- and c-MYC-dependent manner; WDR5 knockdown and OICR-9429 could reduce c-MYC recruitment and cell proliferation, increasing apoptosis and chemosensitivity to cisplatin in vitro and in vivo [14].
EZH2 (enhancer of zeste homolog 2) is the methyltransferase catalytic subunit of the polycomb repressive complex 2 (PRC2), which trimethylates Lysine 27 of histone H3 (H3K27me3) to promote transcriptional repression [158]. In PC models [158], EZH2 inhibition activates a double-stranded RNA–STING (stimulator of interferon genes)–ISGs (interferon-stimulated genes) stress response in tumor cells, upregulating genes involved in antigen presentation, Th1 chemokine signaling, and interferon response, including PD-L1 (dependent on STING activation) [158]. Moreover, EZH2 inhibition substantially increased the intratumoral trafficking of activated CD8+ and CD4+ T cells (decreasing the relative number of regulatory T cells, Tregs) and increased M1 tumor-associated macrophages (TAMs) (decreasing the tumor-promoting M2 macrophages). This pathway reversed the resistance to anti-PD-1 therapy in B6-MYC-CaP PCs in vivo [158].
mRNA translation is modulated by the rate of the elongation phase of protein synthesis through the phosphorylation of eukaryotic elongation factor 2 (eEF2) by its Ca2+-dependent protein kinase (eEF2K), which promotes PD-L1 expression [159].
miRNAs can regulate PD-L1 at a post-transcriptional level. In cell lines, Chen et al. [26] found that miR-15a negatively regulated PD-L1 expression. Moreover, miR15a overexpression promoted the cytotoxicity of CD8+ T cells against PC cells via directly targeting PD-L1, also decreasing tumor cell viability, migration, and invasion. miR-15a mimics downregulated pathways involved in the epithelial–mesenchymal transition (EMT) and RAS/ERK signaling. In contrast, PD-L1 overexpression in miR-15a mimics-transfected PC cells reversed these phenotypes; PD-L1 may influence the tumor-suppressive activity of miR-15a and stimulate multiple malignant phenotypes by activating the RAS/ERK signaling [26]. The long non-coding RNA gene KCNQ1 overlapping transcript 1 (lncRNA KCNQ1OT1) sponged miR-15a to upregulate the expression of PD-L1, thus inhibiting the cytotoxicity of CD8+ T cells and promoting tumor evasion [26]. Knocking down KCNQ1OT1 lowered PD-L1 expression and inhibited the viability, migration, invasion, and EMT of tumor cells, favoring their apoptosis; moreover, it enhanced the cytotoxicity and proliferation of CD8+ T-cells, reducing their apoptosis.
Functional experiments have demonstrated that miR-195 and miR-16 influenced the PD-L1-associated apoptosis in a co-culture model of human PC cell lines and human T cells [73]. miR-195 and miR-16 enhanced the radiotherapy efficacy in PC cell lines by activating the cytotoxic T cell response (repressing T cell dysfunction), inhibiting myeloid-derived suppressor cells (MDSCs) and Tregs, and increasing the secretion of pro-inflammatory cytokines (such as IFN-γ, TNF-α, and IL-2) in the tumor microenvironment through a PD-L1-dependent pathway [73].
All the above-mentioned observations referred to acinar PCs. Epigenetic methylation could regulate the JAK/STAT pathway—which is involved in PD-L1 expression—also in non-acinar PC histotypes. Indeed, the abstract of Sun et al. reported that PD-L1 expression was increased in small cell neuroendocrine PCs (in human cases, PC cell line, and mice model under IFN-γ stimulation); the block of the JAK1/STAT1 pathway inhibited PD-L1 expression, while demethylation suppressed JAK1 signaling [115].

2.3. Epigenetic Regulation of PD-L1 Expression: Studies on Human Patients, Including Data from The Cancer Genome Atlas (TCGA) Database

The epigenetic control of PD-L1 expression has also been confirmed in some studies on human PC tissues, sometimes using data derived from the TCGA database. In these studies, PD-L1 expression was evaluated on tumor tissue by real-time polymerase chain reaction (RT-PCR) analysis [14,26,60,73,90,93] and/or by immunohistochemistry [14,46,83,90,93,116] (Table 3).
Some authors found that normal prostatic tissue showed lower levels of PD-L1 RNA [26] and PD-L1 promoter methylation (mPD-L1) (compared to PC samples) [90].
In the study of Xiong et al. [60], PD-L1 RNA levels were higher in PC metastases than in primary tumor specimens (n = 35), correlating with MLL3 either in their series or in cases derived from the TCGA database (p < 0.01) [60]. MLL3 and PD-L1 RNA levels positively correlated to PSA levels (not Grade Group, age, or stage) [60].
Unlike PD-L1 negative regulators (HDAC1, HDAC2, and HDAC3), the expression ranks of PD-L1 and its positive regulators (EP300, CREBBP, IRF-1, and BRD4) negatively correlated to Grade Group in another study, suggesting an increase of function during cancer progression [116]. PD-L1, EP300, and CREBBP were negatively associated with overall survival. PD-L1 and PD-1 expression inversely correlated to tumor purity and increased tumor-infiltrating immune cells [116].
In a large series [90], high mPD-L1 (p = 0.008) and high PD-L1 protein expression (pePD-L1) (p = 0.002) (analyzed as continuous variables) both correlated to shorter biochemical recurrence-free survival (BRFS) in multivariate analysis (compared to pePD-L1low/mPD-L1low): these results were not confirmed in the validation cohort. Patients with pePD-L1high/mPD-L1low or pePD-L1low/mPD-L1high showed intermediate BRFS. PD-L1 DNA methylation was associated with the pT stage (p < 0.001) and the Grade Group (p = 0.001).
Another study [93] found that high PD-L1 expression and aberrant CXCL12 methylation (mCXCL12) correlated to significantly shorter BRFS than either PD-L1low/mCXCL12normal or PD-L1high/mCXCL12normal cases. The aberrant mCXCL12 group included either hypo- or hyper-methylated cases, which were combined in the analysis. Concordant results were found between radical prostatectomies and biopsies; unlike the mCXCL12 profile, CXCL12 immunohistochemical expression was not associated with the outcome [93].
The novel lncAMPC transcript produced by the RNF165 (RING finger protein 165) gene apparently promoted metastatic behavior and immunosuppression in PCs via LIF/LIFR stimulation. In mouse PC models, PD-L1 immunohistochemical staining positively correlated to the lncAMPC-activated LIF levels, while LIF inhibition weakened the PD-L1-mediated immunosuppression in PC. The TCGA dataset analysis on human patients confirmed that PD-L1 expression was positively associated with lncAMPC-activated LIF levels and RNF165 gene transcripts [108].
The epigenetic control of miRNAs concerning PD-L1 expression has also been investigated in some studies on PC patients. In the series of Tao et al. [73] (n = 40), miR-195 and miR-16 expression inversely correlated to PD-L1, PD-1, CD80, and CTLA-4 levels, showing a potentially positive association with longer BRFS [73]. In silico analysis of GSE21032 dataset (n = 131) confirmed that high miR-195/miR-16 levels were negatively associated with PD-L1 expression: both miRNAs also correlated to longer BRFS [73]. An inverse correlation between miR-15a expression and PD-L1 mRNA has been observed in another cohort of 30 PC tissues [26].
In contrast, miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels, being inversely associated with the methylation of PD-L1 promoter in a large series [90], suggesting that mPD-L1 is correlated to decreased mRNA expression, destabilizing miR-197 and miR-200a-c. miR-570 was only associated with mPD-L1, while miR-34a inversely correlated to mPD-L1 and mRNA expression [90]. miR-513 was not differentially expressed with regard to methylation and PD-L1 mRNA expression [90].
While PD-L1 levels were usually evaluated by RT-PCR analysis, some authors found that miR-424-3p (analyzed by in situ hybridization) significantly correlated to CTLA-4 (p < 0.001) and PD-L1 (p = 0.040) immunohistochemical expression in tumor cells [46,83].
In another series (cohort 1 = 136 PCs + 26 adjacent prostate tissue; cohort 2 = 126 PCs + 19 adjacent prostate tissue), the positivity rate of PD-L1 by immunohistochemistry (clone E1L3N, Cell Signaling Technology) was significantly higher in samples showing WDR5 overexpression: the TCGA database (n = 374) also demonstrated a positive correlation between WDR5 and PD-L1 mRNA levels [14].

3. Discussion

Epigenetic changes may drive drug resistance. Regulation of epigenetic mediators of acquired tumor immune escape (such as EZH2, DNMTs, HDACs, Bromodomain and ExtraTerminal (BET) family members, and Lysine-specific demethylases) may overcome the immunotherapy resistance in PCs [63,77,158,159,160,161]. Indeed, PD-L1 expression is controlled at multiple levels, including genetic aberrations and epigenetic, transcriptional, or post-transcriptional regulations (such as DNA methylation, histone modifications, changes in gene transcription, mRNA stability, miRNAs, etc.) [159].
DNA methylation (mDNA) is involved in cell differentiation and is often aberrantly deregulated in cancers, favoring PC tumorigenesis and progression [5,14,78,90,97]. mDNA analysis is a promising diagnostic tool for specimens with a limited DNA quantity and/or in the case of formalin-fixed paraffin-embedded tissue samples with degraded DNA [90,97]. However, routine tests cannot identify the heterogeneous methylation patterns of the different cell types of a specimen; instead, microdissection techniques may be helpful [90,97].
DNA promoter methylation is frequently correlated to gene silencing [5,14]. In normal tissues, about 80% of CpGs DNA sequences are methylated, while CpG islands in the promoter regions of active genes are hypomethylated. Cancers (such as PC) usually shift the mDNA pattern toward a global hypomethylation, but CpGs in promoter regions of tumor suppressor genes may undergo hypermethylation, resulting in the inhibition of gene expression and gene loss of function. Complex aberrant methylation may also occur. Moreover, genes frequently silenced in the normal human genome (such as “long interspersed nuclear element-1”, LINE-1) can be re-expressed in PC cells [6,7,8,9,10,11,90,97,162,163,164].
The DNMTs family comprises DNA-modifying enzymes epigenetically regulating gene expression: they catalyze the addition of a methyl group to 5-methylcytosine (5mC) in CpG-enriched islands of gene-promoter regions (where they bind with a specific zinc finger domain) [6,7,8,9,10,11,162,163,164]. Cytosine methylation in mammals seems established by the complex recruitment of at least three independently encoded DNMTs (DNMT1, DNMT3a, and DNMT3b) [7,164]. DNMT1 keeps the mDNA pattern during replication, while DNMT3a/3b are de novo methyltransferases. Ten–eleven translocation enzymes can reverse mDNA. The three DNMTs coordinate mRNA expression in normal tissues and overexpression in cancers of various sites (colon, prostate, breast, liver, leukemia, etc.), typically promoting gene silencing. Decreased DNMT1 levels appear to be protective [165,166,167]. In PCs, DNMTs (especially DNMT3a and DNMT3b) were highly expressed, being associated with tumor progression [164]. An assessment of mDNA-based panels along with PSA screening demonstrated a highly predictive value for recurrence detection in PC patients [164].
In some studies, mPD-L1 suppressed PD-L1 expression in PCs [7,90,93]. In a large series, despite some limits, high mPD-L1 seemed an independent prognostic biomarker for BRFS in PC patients after radical prostatectomy, being also associated with the pT stage and Grade Group [90]. DNMT1 and DNMT3b may cooperatively maintain mDNA and gene silencing in cancer cells, synergizing their biological function, improving methylation efficacy, and suppressing PD-L1 expression more efficiently than DNMT3ac alone; this hypothesis was supported by pre-clinical studies using recombinant constructs (expressing the C-terminal domains of DNMT3a and/or DNMT1 fused with a zinc finger domain specifically binding to the PD-L1 promoter) [7].
The C-X-C chemokine receptor type 4 (CXCR4) and its endogenous ligand CXCL12 are expressed in various tumors [168]. They seemed to be involved in favoring androgen-dependent proliferation, tumor cell motility, and metastatic growth in PC [169], co-operating with the PD-1/PD-L1 pathway to suppress anti-cancer immunity [170]. CXCR4 expression favors chemotactic cell migration toward compartments releasing high levels of CXCL12, such as bone marrow (a frequent PC-metastatic site) [171]. Constant CXCL12 production causes CXCR4a downregulation and desensitization, resulting in a resting state of tumor cells and antagonizing the metastatic process [171]. CXCL12 promoter hypermethylation downregulates CXCL12 protein expression in PC, disrupting the cellular feedback internalization of membranous CXCR4 and so favoring tumor cell motility and metastatic potential [93]. In the series of Goltz et al. [93], high PD-L1 expression and aberrant mCXCL12 were associated with significantly shorter BRFS than either PD-L1low/mCXCL12normal or PD-L1high/mCXCL12normal cases.
Epigenetic methylation may regulate the JAK/STAT pathway (involved in PD-L1 expression) also in non-acinar PCs (such as neuroendocrine carcinomas); however, limited data are available [115].
Different cancer types show aberrant expressions of HDACs, representing a promising target for cancer therapy [172]. Androgen receptor (AR) is a driver of PC progression: its downstream signaling events are closely regulated by epigenetic modifications [116]. HDAC inhibition could downregulate AR protein levels and significantly induce PD-L1 expression by increasing the acetylation of the CD274 promoter, resulting in an immune-evasive microenvironment for tumor progression [173].
p300 is a coactivator of AR, regulating its transcriptional program and signaling axis and being involved in PC recurrence and chemoresistance. p300 directly acetylates AR or binds to AR, enhancing its transcriptional activity, inducing the expression of oncogenes, and promoting tumor growth [174]. Moreover, p300 could prevent AR protein degradation [174]. p300 is also involved in PC progression through PD-L1 upregulation, favoring tumor immune escape. The transcription factor IRF-1 could recruit p300 to the CD274 promoter, inducing its transcription via histone acetylation. In an experimental study [116], the p300 inhibitor but not the anti-PD-L1 antibody significantly enhanced the efficacy of HDAC inhibitors on limiting tumor progression by blocking the HDAC inhibition-induced PD-L1 expression. Data on human patients and the TCGA dataset suggested that PD-L1 and p300 expression (unlike HDACs) negatively correlated to the Grade Group and overall survival, favoring an increase of function during cancer progression [116].
A485 (p300/CBP catalytic inhibitor) can decrease the proliferation of hematological tumors and AR-positive PCs [175]. A485 may enhance the efficacy of anti-PD-L1 antibody treatment, reducing the PD-L1 expression and exosomal secretion by PC cell lines; combined treatments inhibited the androgen-independent metastatic tumor growth in syngeneic PC models [116].
HDAC inhibitors have been approved for the treatment of T-cell lymphoma (vorinostat, SAHA; belinostat; and romidepsin) or multiple myeloma (panobinostat and LBH589). They have also been proposed in clinical trials for the treatment of solid malignancies (including PC) despite poor clinical responses in some cases [173,176].
Transcription factors usually bind to distal cis-regulatory regions (enhancers), regulating gene expression in normal conditions and during cancer development or progression [60]. MLL3 and MLL4 are huge molecular weight mono-methyltransferases of the MLL/COMPASS family; their regulation is still largely unknown. MLL3 and MLL4 favor the activity of enhancer regions (such as that of PD-L1) by the methylation of histone H3 on Lysine 4 and through the recruitment of other coactivators (such as p300). PD-L1 and MLL3 seemed positively correlated in PC patients and pre-clinical models [60].
The histone methylation regulator WDR5 is an important component of the SET1/MLL histone-methyltransferase complex and a critical co-activator of oncogenic pathways via the H3K4me3/c-MYC-dependent transcriptional activation of target genes, favoring tumor proliferation, metastases, chemoresistance, and AR-mediated castration-resistance [14]. WDR5 activates cell cycle, DNA repair, anti-apoptosis, and PD-L1 signaling, promoting PC progression; WDR5 seems an independent prognostic factor for progression-free survival and overall survival in PC. In PC cells, the IFN-γ-induced PD-L1 expression is blocked by WDR5 or MLL1 knockdown (not by c-MYC silencing) or by OICR-9429, suppressing proliferation and enhancing apoptosis, sensitivity to cisplatin, and immunotherapy [14].
EZH2 is overexpressed in PCs, contributing to tumor initiation and progression, and negatively regulating interferon-stimulated genes, including Th1-type chemokines, immune checkpoint molecules, and the major histocompatibility complex (MHC) [158]. Increased EZH2 function may favor immunosuppressive tumor microenvironments and immunotherapy resistance [158]. In PC models, EZH2 inhibition upregulated PD-L1 (dependent on STING activation) and other genes involved in antigen presentation, Th1 chemokine signaling, and interferon response. It also increased the intratumoral trafficking of activated CD8+ T cells and M1 TAMs, overall reversing the resistance to anti-PD-1 inhibitors. EZH2 actually regulates CD4+ T and Tregs differentiation [158,177,178]. In Tregs, the loss of EZH2 resulted in the degradation of FOXP3, allowing the reprogramming of Tregs to T-helper cells [179]. It did not change the total number of intratumoral Tregs, but significantly increased the intratumoral CD4+ and CD8+ T cells. EZH2 inhibition in CD8+ T cells may induce PD-1 downregulation and increase cytotoxic activity [179]. MDSCs secrete IL-23 and may activate AR signaling at least in a subset of castration-resistant PCs, representing an important component of the tumor immunosuppressive microenvironment [161]. The EZH2 inhibitor did not dramatically alter intratumoral MDSCs, while significantly reprogrammed TAMs infiltrates, decreasing tumor-promoting M2 TAMs and increasing tumor-inhibiting M1 TAMs [159,161,179].
mRNA translation is regulated by the rate of the elongation phase of protein synthesis through the eEF2K-dependent phosphorylation of eEF2. eEF2K is activated under stress conditions, while it is inhibited by the anabolic mechanistic target of the rapamycin complex 1 (mTORC1) signaling pathway. eEF2K plays a role in cancer cell survival (decreasing protein synthesis and energy/amino acids consumption during nutrient depletion) and migration, angiogenesis, and the synthesis of integrins and other proteins. eEF2K also promotes PD-L1 expression in PC [159].
Bromodomains are protein domains recognizing acetylated Lysine residues on histone tails and other nuclear proteins, promoting gene transcription. The BET protein family comprises four transcriptional coactivators of cell cycle, regulating apoptosis, migration, and invasion (BRD2, BRD3, BRD4 and the testis-specific isoform BRDT). They are frequently overexpressed in various tumors, enhancing the transcription of oncogenic drivers (such as AR and ERG) in PC. BRD4 directly associates with P-TEFb (positive transcription elongation factor b) or interacts with DNA-specific transcription factors (p53, c-MYC, AR, ERG, etc.) [180]. The inhibition of BRD4 reduces the levels of AR-driven target genes in PC, decreasing tumor burden in murine models. BRD4 also regulates immune networks, as it reduces PD-L1 expression by directly binding to the PD-L1 promoter (mediating its transcription). It also increases MHC class I expression and alters the expression of immune-related genes. Moreover, it increases the number of tumor-infiltrating lymphocytes and susceptibility to the CD8+ T cell-mediated cytotoxicity [123,127,180,181,182,183].
In some pre-clinical studies, treatment with JQ1 (bromodomain inhibitor) suppressed PD-L1 expression [123,127]. JQ1 stimulates the antigen presentation pathways promoted by IFN-γ. JQ1 upregulates TAF9, a subunit of the Transcription Factor IID (TFIID) required for the initiation of transcription by RNA Polymerase II. TAF9 associates with CIITA (MHC class II transactivator), forming a complex responsible for MHC class I gene upregulation after IFN-γ stimulation. JQ1 differentially modulates the expression of MHC class I alleles, and it may limit the transcription of inhibitors of RelA/NF-kB, thus enhancing their ability to bind selectively to HLA-A and B and increasing mRNA and protein levels. A combined treatment with bromodomain inhibitors and IFN-γ upregulated TRIM36 (E3 ubiquitin-protein ligase) in a dose-dependent manner. Increased TRIM36 expression was associated with the inhibition of PC proliferation and cell-cycle progression through the inhibition of the MAPK/ERK pathway [123,184]. TRIM36 is also involved in antigen processing [32].
Preclinical models documented resistance to BET inhibitors through largely unknown molecular mechanisms. Speckle-type POZ protein (SPOP) is a E3 ubiquitin ligase of the MATH–BTB family, containing MATH and C-terminal BTB domains, which are both required for BRD4 ubiquitination and degradation. In PC, SPOP or BRD4 mutations confer resistance to BET inhibitors; they inhibit the SPOP-mediated BRD4 destruction by disrupting the SPOP–BRD4 interaction, stabilizing BRD4, and leading to its cooperation with AR, ERG, and other oncogenic transcription factors [180].
miRNAs are small non-coding RNAs regulating gene expression and the metabolic/signaling pathways involved in cell proliferation, differentiation, and survival. They cause mRNA translational inhibition and/or degradation at a post-transcriptional level. miRNAs are potential biomarkers for PC metastasis, apoptotic resistance, and AR signaling disruption [12]. However, miRNA levels vary across different tissues and cancer specimens; heterogeneous expression can be also found in the same tumor [180].
miRNAs regulate PD-L1 expression, modifying the downstream processing of PD-L1 mRNA. Few studies on cell lines and human PC tissues suggested a potential correlation between PD-L1 and some miRNAs (miR-195, miR-15, miR-16, miR-197, miR-200, miR-570, miR-34a, and miR-424) in PC. However, further studies are required.
miR-195, miR-15 and miR-16 are members of the miR-15/-16/-195/-424/-497/-503 family; preclinical models and rare studies on human patients suggested that they downregulate PD-L1 expression in PC. miR-195 inhibits PC progression by targeting the RPS6KB1 gene (encoding the ribosomal protein S6 serine/threonine kinase B1), which is involved in mTOR signaling, promoting protein synthesis, cell growth, and cell proliferation. miR-15a and miR-16 act as tumor suppressors: they downregulate multiple oncogenes (BCL2, MCL1, CCND1, and WNT3A), decreasing PC cell survival, proliferation, invasion, and EMT by targeting TGF-β signaling. These miRNAs also regulate angiogenesis, metastatic potential, chemoresistance, and the tumor microenvironment crosstalk in PC [12,26,69,73,185,186,187,188,189,190,191,192,193].
In a study, miR-195 and miR-16 expression were inversely associated with PD-L1, PD-1, CD80, and CTLA-4 levels, potentially favoring a longer BRFS. They may regulate cytokine secretion in the tumor microenvironment through a PD-L1-dependent pathway and influence the PD-L1-associated apoptosis in PC cell lines [69]. In addition, miR-195 and miR-16 overexpression increases the radiosensitivity of cancer cells; in vitro and in vivo restoration of their expression enhanced radiotherapy via T cell activation in the tumor microenvironment by blocking the PD-L1 immune checkpoint in PC cells, suggesting a synergistic effect of immunotherapy and radiotherapy [73].
LncRNA transcripts may represent useful prognosticators of PC metastasis and proliferation [12]. LncAMPC (a RNF165 transcript) seemed to promote metastasis and immunosuppression in PC by stimulating LIF/LIFR expression: in TCGA datasets, PD-L1 expression positively correlated to the lncAMPC-activated LIF level and RNF165 gene transcripts [104]. Among various targets, miR-15a may bind to the 3′-UTR of PD-L1 and to the lncRNA KCNQ1OT1, located into the same sequence of miR-15a and involved in promoting oncogenic phenotypes and chemoresistance in multiple cancers (colon, lung, breast, liver, etc.). In PC cell lines, KCNQ1OT1 sponged miR-15a, suppressing the miR-15a-mediated inhibition of PD-L1, thus leading to PD-L1 upregulation, the inhibition of CD8+ T-cells cytotoxicity, and the promotion of tumor evasion [26]. The mechanism responsible for KCNQ1OT1 upregulation is still unknown, while the KCNQ1OT1/miR-15a/PD-L1 axis apparently promotes RAS/ERK signaling activation, inducing tumor immune evasion. ERK signaling may directly activate PD-L1 transcription, stabilizing PD-L1 mRNA as in other contexts [26,194,195,196].
miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and were inversely associated with mPD-L1 in a large PC series, suggesting that mPD-L1 was associated with lower mRNA levels destabilizing miR-197 and miR-200a-c [90]. miR-197 expression was rarely investigated in PC: it seems involved in the proliferation, invasion, and metastatic potential of PC cells by regulating integrin subunit alpha V (ITGAV) expression through the STAT5 pathway [197]. miR-197–3p is apparently involved in PI3K/AKT3 signaling, possibly favoring castration-resistance by targeting RAS, RHO, and the SCF complex [198]. It also represses PC cell proliferation by regulating the voltage-dependent anion channel 1 (VDAC1)/AKT/β-catenin axis [199]. Circular RNA itchy E3 ubiquitin-protein ligase upregulation may suppress cell proliferation, promoting apoptosis by targeting miR-197 in PC [200]. Moreover, miR-197 regulates AR protein levels and activity in PC cells [200]. In a PC study, miR-197, miR-346, and miR-361-3p downregulated two AR corepressors (ARHGDIA and TAGLN2) and upregulated the YWHAZ oncogene [201].
The miR-200 family inhibits EMT, cancer growth, invasion, and metastasis via the inhibition of ZEB1 and ZEB2 (transcriptional regulators of E-Cadherin). The loss of the miR-200 family through mDNA results in aggressive PC features. PDGF (involved in EMT) and other growth factors regulate miR-200 expression, while miR-200c directly influences the EGFR and TGF-β receptor signaling [202,203,204]. miR-200b seems significantly downregulated in castration-resistant PCs: miR-200 influences Notch1 expression, and together they regulate EMT progression [205]. miR-200c expression is negatively regulated by ERG in PC cells lines [206]. miR-200 overexpression can reduce PC growth and modulate chemosensitivity [207].
In a PC sudy, miR-570 was only associated with mPD-L1, while miR-34a was inversely correlated to mPD-L1 and mRNA expression. miR-513 was not differentially expressed with regard to methylation and PD-L1 mRNA expression [90]. miR-34a, miR-143, miR-148a, and the miR-200 family are involved in chemoresistance by the inhibition of apoptosis and the activation of signaling pathways. miR-34a expression levels were decreased in androgen-resistant PC3 and DU145 cell lines (vs. androgen-sensitive LNPCa and normal prostatic tissue). TP53 involvement in miR-34a/miR-34c-mediated apoptosis was found in AR+ PC cells: miR-34a expression appeared completely absent in p53-null PC3 cells [208,209].
In a study, miR-424 was highly expressed in metastatic subclones of DU145 cell lines, while the effects on EMT promotion were controversial [210,211]. The PD-1/PD-L1 pathway regulates T cell activation during inflammatory processes, while CTLA-4 is a protein receptor on T cell surface, inhibiting T cell activity during the priming phase; miR-424 may inhibit the PD1/PD-L1 and CD80/CTLA-4 activity, inducing tumor suppression [46]. In PC patients, miR-424–3p expression by in situ hybridization significantly correlated to CTLA-4 (p < 0.001) and PD-L1 (p = 0.040) immunohistochemical positivity of tumor cells. Low miR-424–3p expression was significantly correlated with reduced clinical failure-free survival, aggressive PC features (high Grade Group, large tumor size, perineural and vascular invasion), and CTLA-4/PD-L1 expression on tumor cells, while no association with T cells subsets was found. CTLA-4 was associated with CD3+ and CD4+ T cells and PD-1 expression by tumor cells and stroma (considered separately or as one compartment) [46,83].
Recently, some authors reported that patients with advanced PC release fully functional circulating extracellular vesicles containing miR-424, which facilitate the acquisition of stem-like traits by low tumorigenic cells, favoring metastatic behavior and cancer progression; circulating miR-424-expressing extracellular vesicles were more frequent in patients with metastatic PCs [212,213,214].

4. Materials and Methods

Systematic literature reviews (SLRs) and meta-analyses have become increasingly important in health care as: (1) clinicians read SLRs to keep themselves up to date; (2) they are often a starting point for the development of clinical guidelines or further studies/trials; (3) granting agencies may require the results of SLRs to ensure the justification for research financial support. For these reasons, impacted healthcare journals frequently ask contributing authors to conduct their SLRs according to the PRISMA guidelines (http://www.prisma-statement.org/; accessed on 8 May 2021), which include an evidence-based minimum set of items for reporting and are useful for a critical evaluation of the submitted manuscripts. So, we have conducted our SLR according to these guidelines, searching in multiple databases, as previously described in the various topics/contexts in which they are applicable [215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249].
Our study aimed to answer the following PICO (population, intervention, comparison, outcomes) questions:
  • Population: patients, tumor cell lines, or mouse models included in studies concerning the role of PD-L1 in PC.
  • Intervention: any type of treatment.
  • Comparison: no comparisons are expected.
  • Outcomes: patient’s status at last follow-up (no evidence of disease, alive with disease, or dead of disease), response to therapy, biochemical recurrence-free survival, metastasis-free survival, cancer-specific survival, disease-free survival, clinical failure-free survival, overall survival, and progression-free survival. As regards experiments on PC cell lines and mouse models: any reported effect on cancer and immune cell migration, proliferation, viability, growth, resistance/response to therapy, cytotoxic/anti-tumor activity, PD-L1 expression, and mice/cell line survival.
Study design: retrospective observational study (case series/reports, clinical trials, and experimental studies).
Eligibility/inclusion criteria: experimental studies (tumor cell lines and mouse models) or clinic-pathologic studies on human patients concerning the role PD-L1 in PCs.
Exclusion criteria: tumors not arising from the prostate; non-carcinomatous histotypes; studies not examining PD-L1; cases with uncertain diagnosis; and review articles without new cases.
Information sources and search strategy: we searched for “PD-L1 AND (prostate OR prostatic) AND (adenocarcinoma OR adenocarcinomas OR cancer)” in PubMed (all fields), Web of Science (Topic/Title), and Scopus (Title/Abstract/Keywords) databases. No limitations or additional filters were set. The bibliographic research ended on 8 May 2021.
Study selection: two independent reviewers selected the studies using a 2-step screening method. In the first step, the screening of titles and abstracts was performed to verify the eligibility/inclusion criteria and exclude irrelevant studies. In the second step, full texts of the selected articles were screened by 2 reviewers to verify the eligibility/inclusion criteria and to avoid duplication of the articles. Two other authors screened the reference lists to look for additional relevant publications. Finally, two authors checked the extracted data.
Objects of the systematic review: (1) to update and summarize the literature concerning the role of PD-L1 in PC cells, and (2) to report any information regarding clinic-pathological features, treatment strategies, and patients’ outcomes.
Data collection process/data items: data collection was study-related (authors and year of study publication) and case-related (tumor stage at presentation, Grade Group, type of specimen, treatment, test methods and results of PD-L1 expression, follow-up and outcomes, and experiment type).
Statistical analysis: the collected data were reported as continuous or categorical variables. Categorical variables were summarized by frequencies and percentages; continuous variables were summarized by ranges, mean, and median values. Time-to-recurrence was the time from the primary treatment to the disease recurrence. The survival status was the time from the primary treatment to the last follow-up.
To better present the results of our SLR and discuss the multiple interesting facets of PD-L1 expression by PC in detail, we have divided the presentation and discussion of our results into different articles, representing independent, self-sufficient chapters/parts of our work. They highlight various subtopics, including PD-L1 immunohistochemical expression in PC with a discussion of pre-analytical and interpretation variables; the clinic-pathological correlations of PD-L1 expression in PC; PD-L1 intracellular signaling pathways in PC and the influence of the tumor microenvironment; the data of pre-clinical studies (cell lines and mouse models) about the effects of experimental treatments on PD-L1 expression by PC cells; an investigation of the correlations of PD-L1 expression with the status of the mismatch repair system, BRCA, PTEN, and other main genes in PC; PD-L1 expression in liquid biopsy samples; the information of clinical trials, etc. [250,251,252,253]. We direct the readers to these papers for further details.

5. Conclusions

Epigenetic alterations influence oncogene/oncosuppressor gene expression without changing the DNA sequence. PC displays a complex genetic and epigenetic regulation of cell growth pathways and tumor progression.
In PC cell lines, CpG island methylation of the CD274 promoter negatively regulated PD-L1 expression. Histone modifiers are involved in the PD-L1 transcription rate: the deletion or silencing of histone modifiers (such as MLL3 and MML1) may regulate PD-L1 expression.
Epigenetic drugs could be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. Drugs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) reduced PD-L1 expression, while those favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression.
miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer BRFS. They also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c were positively correlated to PD-L1 mRNA levels and were inversely associated with the methylation of PD-L1 promoters in a large series. miR-570, miR-34a and miR-513 may also be involved in the epigenetic regulation of PC.

Author Contributions

Conceptualization, A.P., M.B., S.C. and M.Z. (Magda Zanelli); methodology, A.P., M.B., S.C., M.R. and M.P.B.; validation, A.P., A.C. and S.C.-P.; formal analysis, A.P., D.D.B., D.M.B. and F.S.; investigation, A.P., S.C. and M.B.; resources, A.P., D.N., E.F., M.Z. (Maurizio Zizzo) and A.S.; data curation, A.P., S.A. and C.C.R.; writing—original draft preparation, A.P., M.B., S.C., F.S. and M.Z. (Magda Zanelli); writing—review and editing, A.P., M.B., S.C., D.D.B., A.B. and E.Z.; visualization, D.D.B. and B.M.; supervision, A.P., A.D.L. and M.L.; project administration, G.S., A.P., G.G., J.G., L.C. and G.C.; funding acquisition, A.P. and M.Z. (Magda Zanelli). All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgment

Andrea Palicelli thanks his family for personal support. Daniel M. Berney is supported by ORCID and a PCUK grant.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Santandrea, G.; Piana, S.; Valli, R.; Zanelli, M.; Gasparini, E.; De Leo, A.; Mandato, V.D.; Palicelli, A. Immunohistochemical Biomarkers as a Surrogate of Molecular Analysis in Ovarian Carcinomas: A Review of the Literature. Diagnostics 2021, 11, 199. [Google Scholar] [CrossRef] [PubMed]
  2. Dai, S.; Jia, R.; Zhang, X.; Fang, Q.; Huang, L. The PD-1/PD-Ls pathway and autoimmune diseases. Cell. Immunol. 2014, 290, 72–79. [Google Scholar] [CrossRef] [PubMed]
  3. Patsoukis, N.; Wang, Q.; Strauss, L.; Boussiotis, V.A. Revisiting the PD-1 pathway. Sci. Adv. 2020, 6, eabd2712. [Google Scholar] [CrossRef]
  4. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Prostate Cancer. Version 2.2021—17 February 2021. Available online: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf (accessed on 29 May 2021).
  5. Antonarakis, E.S.; Piulats, J.M.; Gross-Goupil, M.; Goh, J.; Ojamaa, K.; Hoimes, C.J.; Vaishampayan, U.; Berger, R.; Sezer, A.; Alanko, T.; et al. Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2020, 38, 395–405. [Google Scholar] [CrossRef] [PubMed]
  6. Sharma, S.; Kelly, T.K.; Jones, P.A. Epigenetics in cancer. Carcinogenesis 2010, 31, 27–36. [Google Scholar] [CrossRef]
  7. Li, X.; Wang, Z.; Huang, J.; Luo, H.; Zhu, S.; Yi, H.; Zheng, L.; Hu, B.; Yu, L.; Li, L.; et al. Specific zinc finger-induced methylation of PD-L1 promoter inhibits its expression. FEBS Open Bio 2019, 9, 1063–1070. [Google Scholar] [CrossRef]
  8. Jones, P.A. Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 2012, 13, 484–492. [Google Scholar] [CrossRef]
  9. Eckhardt, F.; Lewin, J.; Cortese, R.; Rakyan, V.K.; Attwood, J.; Burger, M.; Burton, J.; Cox, T.V.; Davies, R.; Down, T.A.; et al. DNA methylation profiling of human chromosomes 6, 20 and 22. Nat. Genet. 2006, 38, 1378–1385. [Google Scholar] [CrossRef] [Green Version]
  10. Lee, S.T.; Wiemels, J.L. Genome-wide CpG island methylation and intergenic demethylation propensities vary among different tumor sites. Nucleic Acids Res. 2016, 44, 1105–1117. [Google Scholar] [CrossRef] [Green Version]
  11. Rhee, I.; Bachman, K.E.; Park, B.H. Dnmt1 and Dnmt 3b cooperate to silence genes in human cancer cells. Nature 2002, 416, 552–556. [Google Scholar] [CrossRef]
  12. Gandhi, J.; Afridi, A.; Vatsia, S.; Joshi, G.; Joshi, G.; Kaplan, S.A.; Smith, N.L.; Khan, S.A. The molecular biology of prostate cancer: Current understanding and clinical implications. Prostate Cancer Prostatic Dis. 2018, 21, 22–36. [Google Scholar] [CrossRef] [PubMed]
  13. Sharma, P.; Pachynski, R.K.; Narayan, V.; Fléchon, A.; Gravis, G.; Galsky, M.D.; Mahammedi, H.; Patnaik, A.; Subudhi, S.K.; Ciprotti, M.; et al. Nivolumab Plus Ipilimumab for Metastatic Castration-Resistant Prostate Cancer: Preliminary Analysis of Patients in the CheckMate 650 Trial. Cancer Cell 2020, 38, 489–499.e3. [Google Scholar] [CrossRef]
  14. Zhou, Q.; Chen, X.; He, H.; Peng, S.; Zhang, Y.; Zhang, J.; Cheng, L.; Liu, S.; Huang, M.; Xie, R.; et al. WD repeat domain 5 promotes chemoresistance and Programmed Death-Ligand 1 expression in prostate cancer. Theranostics 2021, 11, 4809–4824. [Google Scholar] [CrossRef] [PubMed]
  15. Vardaki, I.; Corn, P.; Gentile, E.; Song, J.H.; Madan, N.; Hoang, A.; Parikh, N.; Guerra, L.; Lee, Y.C.; Lin, S.C.; et al. Radium-223 Treatment Increases Immune Checkpoint Expression in Extracellular Vesicles from the Metastatic Prostate Cancer Bone Microenvironment. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2021, 27, 3253–3264. [Google Scholar] [CrossRef] [PubMed]
  16. Shim, K.H.; Kwon, J.E.; Park, S.G.; Choo, S.H.; Kim, S.J.; Kim, S.I. Cell membrane and nuclear expression of programmed death ligand-1 in prostate needle biopsy tissue in prostate cancer patients undergoing primary radiation therapy. Urol. Oncol. 2021, 39, 298.e13–298.e20. [Google Scholar] [CrossRef]
  17. Sun, Y.; Jing, J.; Xu, H.; Xu, L.; Hu, H.; Tang, C.; Liu, S.; Wei, Q.; Duan, R.; Guo, J.; et al. N-cadherin inhibitor creates a microenvironment that protect TILs from immune checkpoints and Treg cells. J. Immunother. Cancer 2021, 9, e002138. [Google Scholar] [CrossRef]
  18. Zavridou, M.; Strati, A.; Bournakis, E.; Smilkou, S.; Tserpeli, V.; Lianidou, E. Prognostic Significance of Gene Expression and DNA Methylation Markers in Circulating Tumor Cells and Paired Plasma Derived Exosomes in Metastatic Castration Resistant Prostate Cancer. Cancers 2021, 13, 780. [Google Scholar] [CrossRef]
  19. Brady, L.; Kriner, M.; Coleman, I.; Morrissey, C.; Roudier, M.; True, L.D.; Gulati, R.; Plymate, S.R.; Zhou, Z.; Birditt, B.; et al. Inter- and intra-tumor heterogeneity of metastatic prostate cancer determined by digital spatial gene expression profiling. Nat. Commun. 2021, 12, 1426. [Google Scholar] [CrossRef] [PubMed]
  20. Zhang, T.; Agarwal, A.; Almquist, R.G.; Runyambo, D.; Park, S.; Bronson, E.; Boominathan, R.; Rao, C.; Anand, M.; Oyekunle, T.; et al. Expression of immune checkpoints on circulating tumor cells in men with metastatic prostate cancer. Biomark. Res. 2021, 9, 14. [Google Scholar] [CrossRef]
  21. Petrylak, D.P.; Loriot, Y.; Shaffer, D.R.; Braiteh, F.; Powderly, J.; Harshman, L.C.; Conkling, P.; Delord, J.P.; Gordon, M.; Kim, J.W.; et al. Safety and Clinical Activity of Atezolizumab in Patients with Metastatic Castration-Resistant Prostate Cancer: A Phase I Study. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2021, 27, 3360–3369. [Google Scholar] [CrossRef]
  22. Imamura, R.; Kitagawa, S.; Kubo, T.; Irie, A.; Kariu, T.; Yoneda, M.; Kamba, T.; Imamura, T. Prostate cancer C5a receptor expression and augmentation of cancer cell proliferation, invasion, and PD-L1 expression by C5a. Prostate 2021, 81, 147–156. [Google Scholar] [CrossRef]
  23. Meng, J.; Zhou, Y.; Lu, X.; Bian, Z.; Chen, Y.; Zhou, J.; Zhang, L.; Hao, Z.; Zhang, M.; Liang, C. Immune response drives outcomes in prostate cancer: Implications for immunotherapy. Mol. Oncol. 2021, 15, 1358–1375. [Google Scholar] [CrossRef] [PubMed]
  24. Wong, J.K.; MacFarlane, A.; Devarajan, K.; Shulman, R.M.; Alpaugh, R.K.; Burbure, N.; Hallman, M.A.; Geynisman, D.M.; Horwitz, E.M.; Campbell, K.; et al. Hypofractionated Short Course Radiation Treatment Results in Systemic Immune Activation and Upregulation of the PD-1/PD-L1 Exhaustion Axis: A Prospective Pilot Study in Early Stage Prostate Cancer Patients. Int. J. Radiat. Oncol. Biol. Phys. 2020, 108, S120. [Google Scholar] [CrossRef]
  25. Graff, J.N.; Beer, T.M.; Alumkal, J.J.; Slottke, R.E.; Redmond, W.L.; Thomas, G.V.; Thompson, R.F.; Wood, M.A.; Koguchi, Y.; Chen, Y.; et al. A phase II single-arm study of pembrolizumab with enzalutamide in men with metastatic castration-resistant prostate cancer progressing on enzalutamide alone. J. Immunother. Cancer 2020, 8, e000642. [Google Scholar] [CrossRef]
  26. Chen, Q.H.; Li, B.; Liu, D.G.; Zhang, B.; Yang, X.; Tu, Y.L. LncRNA KCNQ1OT1 sponges miR-15a to promote immune evasion and malignant progression of prostate cancer via up-regulating PD-L1. Cancer Cell Int. 2020, 20, 394. [Google Scholar] [CrossRef]
  27. Wang, Q.; Ye, Y.; Yu, H.; Lin, S.H.; Tu, H.; Liang, D.; Chang, D.W.; Huang, M.; Wu, X. Immune checkpoint-related serum proteins and genetic variants predict outcomes of localized prostate cancer, a cohort study. Cancer Immunol. Immunother. 2021, 70, 701–712. [Google Scholar] [CrossRef] [PubMed]
  28. Han, H.J.; Li, Y.R.; Roach, M., 3rd; Aggarwal, R. Dramatic response to combination pembrolizumab and radiation in metastatic castration resistant prostate cancer. Ther. Adv. Med. Oncol. 2020, 12, 1758835920936084. [Google Scholar] [CrossRef]
  29. Vicier, C.; Ravi, P.; Kwak, L.; Werner, L.; Huang, Y.; Evan, C.; Loda, M.; Hamid, A.A.; Sweeney, C.J. Association between CD8 and PD-L1 expression and outcomes after radical prostatectomy for localized prostate cancer. Prostate 2021, 81, 50–57. [Google Scholar] [CrossRef]
  30. Ryan, S.T.; Zhang, J.; Burner, D.N.; Liss, M.; Pittman, E.; Muldong, M.; Shabaik, A.; Woo, J.; Basler, N.; Cunha, J.; et al. Neoadjuvant rituximab modulates the tumor immune environment in patients with high risk prostate cancer. J. Transl. Med. 2020, 18, 214. [Google Scholar] [CrossRef]
  31. Sharma, M.; Yang, Z.; Miyamoto, H. Loss of DNA mismatch repair proteins in prostate cancer. Medicine 2020, 99, e20124. [Google Scholar] [CrossRef] [PubMed]
  32. Wagle, M.C.; Castillo, J.; Srinivasan, S.; Holcomb, T.; Yuen, K.C.; Kadel, E.E.; Mariathasan, S.; Halligan, D.L.; Carr, A.R.; Bylesjo, M.; et al. Tumor Fusion Burden as a Hallmark of Immune Infiltration in Prostate Cancer. Cancer Immunol. Res. 2020, 8, 844–850. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Obradovic, A.Z.; Dallos, M.C.; Zahurak, M.L.; Partin, A.W.; Schaeffer, E.M.; Ross, A.E.; Allaf, M.E.; Nirschl, T.R.; Liu, D.; Chapman, C.G.; et al. T-Cell Infiltration and Adaptive Treg Resistance in Response to Androgen Deprivation with or without Vaccination in Localized Prostate Cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2020, 26, 3182–3192. [Google Scholar] [CrossRef] [Green Version]
  34. Goswami, S.; Walle, T.; Cornish, A.E.; Basu, S.; Anandhan, S.; Fernandez, I.; Vence, L.; Blando, J.; Zhao, H.; Yadav, S.S.; et al. Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma. Nat. Med. 2020, 26, 39–46. [Google Scholar] [CrossRef]
  35. Ihle, C.L.; Provera, M.D.; Straign, D.M.; Smith, E.E.; Edgerton, S.M.; Van Bokhoven, A.; Lucia, M.S.; Owens, P. Distinct tumor microenvironments of lytic and blastic bone metastases in prostate cancer patients. J. Immunother. Cancer 2019, 7, 293. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Ross, A.E.; Hurley, P.J.; Tran, P.T.; Rowe, S.P.; Benzon, B.; Neal, T.O.; Chapman, C.; Harb, R.; Milman, Y.; Trock, B.J.; et al. A pilot trial of pembrolizumab plus prostatic cryotherapy for men with newly diagnosed oligometastatic hormone-sensitive prostate cancer. Prostate Cancer Prostatic Dis. 2020, 23, 184–193. [Google Scholar] [CrossRef] [PubMed]
  37. Bryce, A.H.; Dronca, R.S.; Costello, B.A.; Infante, J.R.; Ames, T.D.; Jimeno, J.; Karp, D.D. PT-112 in advanced metastatic castrate-resistant prostate cancer (mCRPC), as monotherapy or in combination with PD-L1 inhibitor avelumab: Findings from two phase I studies. J. Clin. Oncol. 2020, 38 (Suppl. S6), 83. [Google Scholar] [CrossRef]
  38. Abdul Sater, H.; Marté, J.L.; Donahue, R.N.; Walter-Rodriguez, B.; Heery, C.R.; Steinberg, S.M.; Cordes, L.M.; Chun, G.; Karzai, F.; Bilusic, M.; et al. Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer. J. Immunother. Cancer 2020, 8, e000655. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Sharma, M.; Yang, Z.; Miyamoto, H. Immunohistochemistry of immune checkpoint markers PD-1 and PD-L1 in prostate cancer. Medicine 2019, 98, e17257. [Google Scholar] [CrossRef] [PubMed]
  40. Shaw, K.; Calagua, C.; Russo, J.; Einstein, D.; Balk, S.; Ye, H. Tumor PD-L1 Expression is Detected in a Significant Subset of High-Risk Localized and Metastatic Prostate Cancer but is Rare in Ductal Subtype. Mod. Pathol. 2019, 32, 143–144. [Google Scholar]
  41. Matveev, V.B.; Kirichek, A.A.; Safronova, V.M.; Khafizov, K.O.; Filippova, M.G.; Lyubchenko, L.N. Impact of PD-L1 status on the long-term outcomes of radical treatment of patients with prostate cancer. Urologiia 2019, 4, 51–57. [Google Scholar] [CrossRef]
  42. Matveev, V.; Kirichek, A.; Safronova, V.; Kokosadze, N.; Khalmurzaev, O.; Kamolov, B.; Liubchenko, L. The prognostic value of tumor PD-L1 status in patients with metastatic prostate cancer. Cancer Urol. 2019, 15, 57–65. [Google Scholar] [CrossRef]
  43. Iacovelli, R.; Ciccarese, C.; Brunelli, M.; Bogina, G.; Munari, E.; Bimbatti, D.; Mosillo, C.; Fantinel, E.; Bria, E.; Martignoni, G.; et al. PD-L1 Expression in De Novo Metastatic Castration-sensitive Prostate Cancer. J. Immunother. 2019, 42, 269–273. [Google Scholar] [CrossRef]
  44. Kazantseva, M.; Mehta, S.; Eiholzer, R.A.; Gimenez, G.; Bowie, S.; Campbell, H.; Reily-Bell, A.L.; Roth, I.; Ray, S.; Drummond, C.J.; et al. The Δ133p53β isoform promotes an immunosuppressive environment leading to aggressive prostate cancer. Cell Death Dis. 2019, 10, 631. [Google Scholar] [CrossRef] [PubMed]
  45. Lindh, C.; Kis, L.; Delahunt, B.; Samaratunga, H.; Yaxley, J.; Wiklund, N.P.; Clements, M.; Egevad, L. PD-L1 expression and deficient mismatch repair in ductal adenocarcinoma of the prostate. Acta Pathol. Microbiol. Immunol. Scand. 2019, 127, 554–560. [Google Scholar] [CrossRef]
  46. Richardsen, E.; Andersen, S.; Al-Saad, S.; Rakaee, M.; Nordby, Y.; Pedersen, M.I.; Ness, N.; Ingebriktsen, L.M.; Fassina, A.; Taskén, K.A.; et al. Low Expression of miR-424-3p is Highly Correlated with Clinical Failure in Prostate Cancer. Sci. Rep. 2019, 9, 10662. [Google Scholar] [CrossRef] [PubMed]
  47. Xian, P.; Ge, D.; Wu, V.J.; Patel, A.; Tang, W.W.; Wu, X.; Zhang, K.; Li, L.; You, Z. PD-L1 instead of PD-1 status is associated with the clinical features in human primary prostate tumors. Am. J. Clin. Exp. Urol. 2019, 7, 159–169. [Google Scholar] [PubMed]
  48. Li, H.; Wang, Z.; Zhang, Y.; Sun, G.; Ding, B.; Yan, L.; Liu, H.; Guan, W.; Hu, Z.; Wang, S.; et al. The Immune Checkpoint Regulator PDL1 is an Independent Prognostic Biomarker for Biochemical Recurrence in Prostate Cancer Patients Following Adjuvant Hormonal Therapy. J. Cancer 2019, 10, 3102–3111. [Google Scholar] [CrossRef]
  49. Pal, S.K.; Moreira, D.; Won, H.; White, S.W.; Duttagupta, P.; Lucia, M.; Jones, J.; Hsu, J.; Kortylewski, M. Reduced T-cell Numbers and Elevated Levels of Immunomodulatory Cytokines in Metastatic Prostate Cancer Patients De Novo Resistant to Abiraterone and/or Enzalutamide Therapy. Int. J. Mol. Sci. 2019, 20, 1831. [Google Scholar] [CrossRef] [Green Version]
  50. Abida, W.; Cheng, M.L.; Armenia, J.; Middha, S.; Autio, K.A.; Vargas, H.A.; Rathkopf, D.; Morris, M.J.; Danila, D.C.; Slovin, S.F.; et al. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol. 2019, 5, 471–478. [Google Scholar] [CrossRef] [PubMed]
  51. Zhao, S.G.; Lehrer, J.; Chang, S.L.; Das, R.; Erho, N.; Liu, Y.; Sjöström, M.; Den, R.B.; Freedland, S.J.; Klein, E.A.; et al. The Immune Landscape of Prostate Cancer and Nomination of PD-L2 as a Potential Therapeutic Target. J. Nat. Cancer Inst. 2019, 111, 301–310. [Google Scholar] [CrossRef]
  52. Scimeca, M.; Bonfiglio, R.; Urbano, N.; Cerroni, C.; Anemona, L.; Montanaro, M.; Fazi, S.; Schillaci, O.; Mauriello, A.; Bonanno, E. Programmed death ligand 1 expression in prostate cancer cells is associated with deep changes of the tumor inflammatory infiltrate composition. Urol. Oncol. 2019, 37, 297.e19–297.e31. [Google Scholar] [CrossRef]
  53. Jung, K.H.; LoRusso, P.; Burris, H.; Gordon, M.; Bang, Y.J.; Hellmann, M.D.; Cervantes, A.; Ochoa de Olza, M.; Marabelle, A.; Hodi, F.S.; et al. Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2019, 25, 3220–3228. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Mo, R.J.; Han, Z.D.; Liang, Y.K.; Ye, J.H.; Wu, S.L.; Lin, S.X.; Zhang, Y.Q.; Song, S.D.; Jiang, F.N.; Zhong, W.D.; et al. Expression of PD-L1 in tumor-associated nerves correlates with reduced CD8(+) tumor-associated lymphocytes and poor prognosis in prostate cancer. Int. J. Cancer 2019, 144, 3099–3110. [Google Scholar] [CrossRef] [PubMed]
  55. Papanicolau-Sengos, A.; Yang, Y.; Pabla, S.; Lenzo, F.L.; Kato, S.; Kurzrock, R.; DePietro, P.; Nesline, M.; Conroy, J.; Glenn, S.; et al. Identification of targets for prostate cancer immunotherapy. Prostate 2019, 79, 498–505. [Google Scholar] [CrossRef] [PubMed]
  56. Von Hardenberg, J.; Hartmann, S.; Nitschke, K.; Worst, T.S.; Ting, S.; Reis, H.; Nuhn, P.; Weis, C.A.; Erben, P. Programmed Death Ligand 1 (PD-L1) Status and Tumor-Infiltrating Lymphocytes in Hot Spots of Primary and Liver Metastases in Prostate Cancer with Neuroendocrine Differentiation. Clin. Genitourin. Cancer 2019, 17, 145–153.e5. [Google Scholar] [CrossRef] [PubMed]
  57. Jin, X.; Ding, D.; Yan, Y.; Li, H.; Wang, B.; Ma, L.; Ye, Z.; Ma, T.; Wu, Q.; Rodrigues, D.N.; et al. Phosphorylated RB Promotes Cancer Immunity by Inhibiting NF-κB Activation and PD-L1 Expression. Mol. Cell 2019, 73, 22–35.e6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Karzai, F.; VanderWeele, D.; Madan, R.A.; Owens, H.; Cordes, L.M.; Hankin, A.; Couvillon, A.; Nichols, E.; Bilusic, M.; Beshiri, M.L.; et al. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J. Immunother. Cancer 2018, 6, 141. [Google Scholar] [CrossRef]
  59. Richter, I.; Jirasek, T.; Havlickova, I.; Curcikova, R.; Samal, V.; Dvorak, J.; Bartos, J. The expression of PD-L1 in patients with castrate prostate cancer treated with enzalutamide. J. Balk. Union Oncol. 2018, 23, 1796–1802. [Google Scholar]
  60. Xiong, W.; Deng, H.; Huang, C.; Zen, C.; Jian, C.; Ye, K.; Zhong, Z.; Zhao, X.; Zhu, L. MLL3 enhances the transcription of PD-L1 and regulates anti-tumor immunity. Biochim. Biophys. Acta Mol. Basis Dis. 2019, 1865, 454–463. [Google Scholar] [CrossRef]
  61. Hahn, E.; Liu, S.K.; Vesprini, D.; Xu, B.; Downes, M.R. Immune infiltrates and PD-L1 expression in treatment-naïve acinar prostatic adenocarcinoma: An exploratory analysis. J. Clin. Pathol. 2018, 71, 1023–1027. [Google Scholar] [CrossRef] [PubMed]
  62. Redman, J.M.; Steinberg, S.M.; Gulley, J.L. Quick efficacy seeking trial (QuEST1): A novel combination immunotherapy study designed for rapid clinical signal assessment metastatic castration-resistant prostate cancer. J. Immunother. Cancer 2018, 6, 91. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Nava Rodrigues, D.; Rescigno, P.; Liu, D.; Yuan, W.; Carreira, S.; Lambros, M.B.; Seed, G.; Mateo, J.; Riisnaes, R.; Mullane, S.; et al. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J. Clin. Investig. 2018, 128, 4441–4453. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Salvi, S.; Casadio, V.; Martignano, F.; Gurioli, G.; Tumedei, M.M.; Calistri, D.; Gunelli, R.; Costantini, M. Carcinosarcoma of the prostate: Case report with molecular and histological characterization. Int. J. Biol. Markers 2018, 33, 540–544. [Google Scholar] [CrossRef] [Green Version]
  65. Wang, C.; Hahn, E.; Slodkowska, E.; Eskander, A.; Enepekides, D.; Higgins, K.; Vesprini, D.; Liu, S.K.; Downes, M.R.; Xu, B. Reproducibility of PD-L1 immunohistochemistry interpretation across various types of genitourinary and head/neck carcinomas, antibody clones, and tissue types. Hum. Pathol. 2018, 82, 131–139. [Google Scholar] [CrossRef] [PubMed]
  66. Hansen, A.R.; Massard, C.; Ott, P.A.; Haas, N.B.; Lopez, J.S.; Ejadi, S.; Wallmark, J.M.; Keam, B.; Delord, J.P.; Aggarwal, R.; et al. Pembrolizumab for advanced prostate adenocarcinoma: Findings of the KEYNOTE-028 study. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2018, 29, 1807–1813. [Google Scholar] [CrossRef]
  67. McNeel, D.G.; Eickhoff, J.C.; Wargowski, E.; Zahm, C.; Staab, M.J.; Straus, J.; Liu, G. Concurrent, but not sequential, PD-1 blockade with a DNA vaccine elicits anti-tumor responses in patients with metastatic, castration-resistant prostate cancer. Oncotarget 2018, 9, 25586–25596. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Ishiba, T.; Hoffmann, A.C.; Usher, J.; Elshimali, Y.; Sturdevant, T.; Dang, M.; Jaimes, Y.; Tyagi, R.; Gonzales, R.; Grino, M.; et al. Frequencies and expression levels of programmed death ligand 1 (PD-L1) in circulating tumor RNA (ctRNA) in various cancer types. Biochem. Biophys. Res. Commun. 2018, 500, 621–625. [Google Scholar] [CrossRef] [PubMed]
  69. Xu, L.J.; Ma, Q.; Zhu, J.; Li, J.; Xue, B.X.; Gao, J.; Sun, C.Y.; Zang, Y.C.; Zhou, Y.B.; Yang, D.R.; et al. Combined inhibition of JAK1,2/Stat3-PD-L1 signaling pathway suppresses the immune escape of castration-resistant prostate cancer to NK cells in hypoxia. Mol. Med. Rep. 2018, 17, 8111–8120. [Google Scholar] [CrossRef] [Green Version]
  70. Haffner, M.C.; Guner, G.; Taheri, D.; Netto, G.J.; Palsgrove, D.N.; Zheng, Q.; Guedes, L.B.; Kim, K.; Tsai, H.; Esopi, D.M.; et al. Comprehensive Evaluation of Programmed Death-Ligand 1 Expression in Primary and Metastatic Prostate Cancer. Am. J. Pathol. 2018, 188, 1478–1485. [Google Scholar] [CrossRef] [Green Version]
  71. Nagaputra, J.; Thike, A.A.; Koh, V. Loss of Androgen Receptor Accompained by Paucity of PD-L1 in Prostate Cancer is Associated with Clinical Relapse. USCAP 2018 Abstracts: Genitourinary Pathology (894–1126). Meeting Abstract: 1033. Mod. Pathol. 2018, 31, 323–403. [Google Scholar]
  72. Tu, Y.N.; Tong, W.L.; Yavorski, J.M.; Blanck, G. Immunogenomics: A Negative Prostate Cancer Outcome Associated with TcR-γ/δ Recombinations. Cancer Microenviron. Off. J. Int. Cancer Microenviron. Soc. 2018, 11, 41–49. [Google Scholar] [CrossRef]
  73. Tao, Z.; Xu, S.; Ruan, H.; Wang, T.; Song, W.; Qian, L.; Chen, K. MiR-195/-16 Family Enhances Radiotherapy via T Cell Activation in the Tumor Microenvironment by Blocking the PD-L1 Immune Checkpoint. Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol. 2018, 48, 801–814. [Google Scholar] [CrossRef] [PubMed]
  74. Budczies, J.; Denkert, C.; Győrffy, B.; Schirmacher, P.; Stenzinger, A. Chromosome 9p copy number gains involving PD-L1 are associated with a specific proliferation and immune-modulating gene expression program active across major cancer types. BMC Med. Genom. 2017, 10, 74. [Google Scholar] [CrossRef] [Green Version]
  75. Fankhauser, C.D.; Schüffler, P.J.; Gillessen, S.; Omlin, A.; Rupp, N.J.; Rueschoff, J.H.; Hermanns, T.; Poyet, C.; Sulser, T.; Moch, H.; et al. Comprehensive immunohistochemical analysis of PD-L1 shows scarce expression in castration-resistant prostate cancer. Oncotarget 2018, 9, 10284–10293. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Truillet, C.; Oh, H.L.J.; Yeo, S.P.; Lee, C.Y.; Huynh, L.T.; Wei, J.; Parker, M.F.L.; Blakely, C.; Sevillano, N.; Wang, Y.H.; et al. Imaging PD-L1 Expression with ImmunoPET. Bioconj. Chem. 2018, 29, 96–103. [Google Scholar] [CrossRef] [PubMed]
  77. Zhang, J.; Bu, X.; Wang, H.; Zhu, Y.; Geng, Y.; Nihira, N.T.; Tan, Y.; Ci, Y.; Wu, F.; Dai, X.; et al. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 2018, 553, 91–95. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Chen, Y.P.; Zhang, Y.; Lv, J.W.; Li, Y.Q.; Wang, Y.Q.; He, Q.M.; Yang, X.J.; Sun, Y.; Mao, Y.P.; Yun, J.P.; et al. Genomic Analysis of Tumor Microenvironment Immune Types across 14 Solid Cancer Types: Immunotherapeutic Implications. Theranostics 2017, 7, 3585–3594. [Google Scholar] [CrossRef] [PubMed]
  79. Calagua, C.; Russo, J.; Sun, Y.; Schaefer, R.; Lis, R.; Zhang, Z.; Mahoney, K.; Bubley, G.J.; Loda, M.; Taplin, M.E.; et al. Expression of PD-L1 in Hormone-naïve and Treated Prostate Cancer Patients Receiving Neoadjuvant Abiraterone Acetate plus Prednisone and Leuprolide. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2017, 23, 6812–6822. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Schott, D.S.; Pizon, M.; Pachmann, U.; Pachmann, K. Sensitive detection of PD-L1 expression on circulating epithelial tumor cells (CETCs) could be a potential biomarker to select patients for treatment with PD-1/PD-L1 inhibitors in early and metastatic solid tumors. Oncotarget 2017, 8, 72755–72772. [Google Scholar] [CrossRef] [Green Version]
  81. Petitprez, F.; Fossati, N.; Vano, Y.; Freschi, M.; Becht, E.; Lucianò, R.; Calderaro, J.; Guédet, T.; Lacroix, L.; Rancoita, P.M.V.; et al. PD-L1 Expression and CD8(+) T-cell Infiltrate are Associated with Clinical Progression in Patients with Node-positive Prostate Cancer. Eur. Urol. Focus 2019, 5, 192–196. [Google Scholar] [CrossRef]
  82. Li, G.; Ross, J.; Yang, X. Mismatch Repair (MMR) Deficiency and PD-L1 Expression in the Prostatic Ductal Adenocarcinoma. Mod. Pathol. 2019, 32, 91. [Google Scholar]
  83. Ness, N.; Andersen, S.; Khanehkenari, M.R.; Nordbakken, C.V.; Valkov, A.; Paulsen, E.E.; Nordby, Y.; Bremnes, R.M.; Donnem, T.; Busund, L.T.; et al. The prognostic role of immune checkpoint markers programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) in a large, multicenter prostate cancer cohort. Oncotarget 2017, 8, 26789–26801. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Baas, W.; Gershburg, S.; Dynda, D.; Delfino, K.; Robinson, K.; Nie, D.; Yearley, J.H.; Alanee, S. Immune Characterization of the Programmed Death Receptor Pathway in High Risk Prostate Cancer. Clin. Genitourin. Cancer 2017, 15, 577–581. [Google Scholar] [CrossRef] [PubMed]
  85. Gao, J.; Ward, J.F.; Pettaway, C.A.; Shi, L.Z.; Subudhi, S.K.; Vence, L.M.; Zhao, H.; Chen, J.; Chen, H.; Efstathiou, E.; et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat. Med. 2017, 23, 551–555. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Lu, X.; Horner, J.W.; Paul, E.; Shang, X.; Troncoso, P.; Deng, P.; Jiang, S.; Chang, Q.; Spring, D.J.; Sharma, P.; et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature 2017, 543, 728–732. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Tretiakova, M.; Fulton, R.; Kocherginsky, M. Comparison of 4 PD-L1 Antibodies in 560 Kidney, Bladder and Prostate Cancers. Mod. Pathol. 2017, 30, 210–271. [Google Scholar]
  88. Najjar, S.N.; Kallakury, B.V.S.; Sheehan, C.E. Infrequent PD-L1 Protetin Expression and Gene Amplification in Prostatic Adenocarcinomas (PACs). Mod. Pathol. 2017, 30, 246A. [Google Scholar]
  89. Hashimoto, Y.; Imai, A.; Hatakeyama, S.; Yoneyama, T.; Koie, T.; Ohyama, C. PD-L1 over expression may predict disease aggressiveness in prostate cancer. Meeting Abstract: 291P. Ann. Oncol. 2016, 27, ix91–ix92. [Google Scholar] [CrossRef]
  90. Gevensleben, H.; Holmes, E.E.; Goltz, D.; Dietrich, J.; Sailer, V.; Ellinger, J.; Dietrich, D.; Kristiansen, G. PD-L1 promoter methylation is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients following radical prostatectomy. Oncotarget 2016, 7, 79943–79955. [Google Scholar] [CrossRef]
  91. Zhou, Q.Z.; Liu, C.D.; Yang, J.K.; Guo, W.B.; Zhou, J.H.; Bian, J. Changed percentage of myeloid-derived suppressor cells in the peripheral blood of prostate cancer patients and its clinical implication. Zhonghua Nan Ke Xue Natl. J. Androl. 2016, 22, 963–967. [Google Scholar]
  92. Sharma, V.; Dong, H.; Kwon, E.; Karnes, R.J. Positive Pelvic Lymph Nodes in Prostate Cancer Harbor Immune Suppressor Cells to Impair Tumor-reactive T Cells. Eur. Urol. Focus 2018, 4, 75–79. [Google Scholar] [CrossRef] [PubMed]
  93. Goltz, D.; Holmes, E.E.; Gevensleben, H.; Sailer, V.; Dietrich, J.; Jung, M.; Röhler, M.; Meller, S.; Ellinger, J.; Kristiansen, G.; et al. CXCL12 promoter methylation and PD-L1 expression as prognostic biomarkers in prostate cancer patients. Oncotarget 2016, 7, 53309–53320. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Graff, J.N.; Alumkal, J.J.; Drake, C.G.; Thomas, G.V.; Redmond, W.L.; Farhad, M.; Cetnar, J.P.; Ey, F.S.; Bergan, R.C.; Slottke, R.; et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget 2016, 7, 52810–52817. [Google Scholar] [CrossRef] [Green Version]
  95. Satelli, A.; Batth, I.S.; Brownlee, Z.; Rojas, C.; Meng, Q.H.; Kopetz, S.; Li, S. Potential role of nuclear PD-L1 expression in cell-surface vimentin positive circulating tumor cells as a prognostic marker in cancer patients. Sci. Rep. 2016, 6, 28910. [Google Scholar] [CrossRef] [PubMed]
  96. Massari, F.; Ciccarese, C.; Caliò, A.; Munari, E.; Cima, L.; Porcaro, A.B.; Novella, G.; Artibani, W.; Sava, T.; Eccher, A.; et al. Magnitude of PD-1, PD-L1 and T Lymphocyte Expression on Tissue from Castration-Resistant Prostate Adenocarcinoma: An Exploratory Analysis. Target. Oncol. 2016, 11, 345–351. [Google Scholar] [CrossRef]
  97. Gevensleben, H.; Dietrich, D.; Golletz, C.; Steiner, S.; Jung, M.; Thiesler, T.; Majores, M.; Stein, J.; Uhl, B.; Müller, S.; et al. The Immune Checkpoint Regulator PD-L1 Is Highly Expressed in Aggressive Primary Prostate Cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2016, 22, 1969–1977. [Google Scholar] [CrossRef] [Green Version]
  98. Martin, A.M.; Nirschl, T.R.; Nirschl, C.J.; Francica, B.J.; Kochel, C.M.; van Bokhoven, A.; Meeker, A.K.; Lucia, M.S.; Anders, R.A.; DeMarzo, A.M.; et al. Paucity of PD-L1 expression in prostate cancer: Innate and adaptive immune resistance. Prostate Cancer Prostatic Dis. 2015, 18, 325–332. [Google Scholar] [CrossRef] [Green Version]
  99. Shalapour, S.; Font-Burgada, J.; Di Caro, G.; Zhong, Z.; Sanchez-Lopez, E.; Dhar, D.; Willimsky, G.; Ammirante, M.; Strasner, A.; Hansel, D.E.; et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 2015, 521, 94–98. [Google Scholar] [CrossRef]
  100. Bishop, J.L.; Sio, A.; Angeles, A.; Roberts, M.E.; Azad, A.A.; Chi, K.N.; Zoubeidi, A. PD-L1 is highly expressed in Enzalutamide resistant prostate cancer. Oncotarget 2015, 6, 234–242. [Google Scholar] [CrossRef] [Green Version]
  101. Spary, L.K.; Salimu, J.; Webber, J.P.; Clayton, A.; Mason, M.D.; Tabi, Z. Tumor stroma-derived factors skew monocyte to dendritic cell differentiation toward a suppressive CD14(+) PD-L1(+) phenotype in prostate cancer. Oncoimmunology 2014, 3, e955331. [Google Scholar] [CrossRef] [Green Version]
  102. Taube, J.M. Unleashing the immune system: PD-1 and PD-Ls in the pre-treatment tumor microenvironment and correlation with response to PD-1/PD-L1 blockade. Oncoimmunology 2014, 3, e963413. [Google Scholar] [CrossRef] [Green Version]
  103. Taube, J.M.; Klein, A.; Brahmer, J.R.; Xu, H.; Pan, X.; Kim, J.H.; Chen, L.; Pardoll, D.M.; Topalian, S.L.; Anders, R.A. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2014, 20, 5064–5074. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Topalian, S.L.; Hodi, F.S.; Brahmer, J.R.; Gettinger, S.N.; Smith, D.C.; McDermott, D.F.; Powderly, J.D.; Carvajal, R.D.; Sosman, J.A.; Atkins, M.B.; et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 2012, 366, 2443–2454. [Google Scholar] [CrossRef]
  105. Dulos, J.; Carven, G.J.; van Boxtel, S.J.; Evers, S.; Driessen-Engels, L.J.; Hobo, W.; Gorecka, M.A.; de Haan, A.F.; Mulders, P.; Punt, C.J.; et al. PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer. J. Immunother. 2012, 35, 169–178. [Google Scholar] [CrossRef] [PubMed]
  106. Zhou, J.E.; Yu, J.; Wang, Y.; Wang, H.; Wang, J.; Wang, Y.; Yu, L.; Yan, Z. ShRNA-mediated silencing of PD-1 augments the efficacy of chimeric antigen receptor T cells on subcutaneous prostate and leukemia xenograft. Biomed. Pharmacother. Biomed. Pharmacother. 2021, 137, 111339. [Google Scholar] [CrossRef] [PubMed]
  107. Wu, Y.; Xie, J.; Jin, X.; Lenchine, R.V.; Wang, X.; Fang, D.M.; Nassar, Z.D.; Butler, L.M.; Li, J.; Proud, C.G. eEF2K enhances expression of PD-L1 by promoting the translation of its mRNA. Biochem. J. 2020, 477, 4367–4381. [Google Scholar] [CrossRef] [PubMed]
  108. Zhang, W.; Shi, X.; Chen, R.; Zhu, Y.; Peng, S.; Chang, Y.; Nian, X.; Xiao, G.; Fang, Z.; Li, Y.; et al. Novel Long Non-coding RNA lncAMPC Promotes Metastasis and Immunosuppression in Prostate Cancer by Stimulating LIF/LIFR Expression. Mol. Ther. J. Am. Soc. Gene Ther. 2020, 28, 2473–2487. [Google Scholar] [CrossRef] [PubMed]
  109. Rennier, K.; Shin, W.J.; Krug, E.; Virdi, G.; Pachynski, R.K. Chemerin Reactivates PTEN and Suppresses PD-L1 in Tumor Cells via Modulation of a Novel CMKLR1-mediated Signaling Cascade. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2020, 26, 5019–5035. [Google Scholar] [CrossRef] [PubMed]
  110. Philippou, Y.; Sjoberg, H.T.; Murphy, E.; Alyacoubi, S.; Jones, K.I.; Gordon-Weeks, A.N.; Phyu, S.; Parkes, E.E.; Gillies McKenna, W.; Lamb, A.D.; et al. Impacts of combining anti-PD-L1 immunotherapy and radiotherapy on the tumour immune microenvironment in a murine prostate cancer model. Br. J. Cancer 2020, 123, 1089–1100. [Google Scholar] [CrossRef]
  111. Wang, B.; Sun, L.; Yuan, Z.; Tao, Z. Wee1 kinase inhibitor AZD1775 potentiates CD8+ T cell-dependent antitumour activity via dendritic cell activation following a single high dose of irradiation. Med. Oncol. 2020, 37, 66. [Google Scholar] [CrossRef] [PubMed]
  112. Papaevangelou, E.; Smolarek, D.; Smith, R.A.; Dasgupta, P.; Galustian, C. Targeting Prostate Cancer Using Intratumoral Cytotopically Modified Interleukin-15 Immunotherapy in a Syngeneic Murine Model. ImmunoTargets Ther. 2020, 9, 115–130. [Google Scholar] [CrossRef] [PubMed]
  113. Wei, J.; Wang, Y.H.; Lee, C.Y.; Truillet, C.; Oh, D.Y.; Xu, Y.; Ruggero, D.; Flavell, R.R.; VanBrocklin, H.F.; Seo, Y.; et al. An Analysis of Isoclonal Antibody Formats Suggests a Role for Measuring PD-L1 with Low Molecular Weight PET Radiotracers. Mol. Imaging Biol. 2020, 22, 1553–1561. [Google Scholar] [CrossRef] [PubMed]
  114. Ding, H.; Wang, Z.; Pascal Laura, E.; Chen, W.; Wang, Z.; Wang, Z. Ell2 Deficiency Upregulates Pd-L1 Expression via Jak2 Signaling in Prostate Cancer Cells. Meeting Abstract: MP51-12. J. Urol. 2020, 203 (Suppl. S4), e768. [Google Scholar]
  115. Sun, Y.; Wei, Q.; Huang, J.; Yang, L. Methylation Can Regulate the Expression of Pd-L1 in Small Cell Prostate Cancer. Meeting Abstract: MP16-12. J. Urol. 2020, 203 (Suppl. S4), e219–e220. [Google Scholar]
  116. Liu, J.; He, D.; Cheng, L.; Huang, C.; Zhang, Y.; Rao, X.; Kong, Y.; Li, C.; Zhang, Z.; Liu, J.; et al. p300/CBP inhibition enhances the efficacy of programmed death-ligand 1 blockade treatment in prostate cancer. Oncogene 2020, 39, 3939–3951. [Google Scholar] [CrossRef]
  117. Yamazaki, T.; Buqué, A.; Ames, T.D.; Galluzzi, L. PT-112 induces immunogenic cell death and synergizes with immune checkpoint blockers in mouse tumor models. Oncoimmunology 2020, 9, 1721810. [Google Scholar] [CrossRef] [Green Version]
  118. Zhang, X.; Chen, H.; Li, G.; Zhou, X.; Shi, Y.; Zou, F.; Chen, Y.; Gao, J.; Yang, S.; Wu, S.; et al. Increased Tim-3 expression on TILs during treatment with the Anchored GM-CSF vaccine and anti-PD-1 antibodies is inversely correlated with response in prostate cancer. J. Cancer 2020, 11, 648–656. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Wang, B.; Zhou, Y.; Zhang, J.; Jin, X.; Wu, H.; Huang, H. Fructose-1,6-bisphosphatase loss modulates STAT3-dependent expression of PD-L1 and cancer immunity. Theranostics 2020, 10, 1033–1045. [Google Scholar] [CrossRef]
  120. Orme, J.J.; Jazieh, K.A.; Xie, T.; Harrington, S.; Liu, X.; Ball, M.; Madden, B.; Charlesworth, M.C.; Azam, T.U.; Lucien, F.; et al. ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance. Oncoimmunology 2020, 9, 1744980. [Google Scholar] [CrossRef] [Green Version]
  121. Gan, S.; Ye, J.; Li, J.; Hu, C.; Wang, J.; Xu, D.; Pan, X.; Chu, C.; Chu, J.; Zhang, J.; et al. LRP11 activates β-catenin to induce PD-L1 expression in prostate cancer. J. Drug Target. 2020, 28, 508–515. [Google Scholar] [CrossRef]
  122. Choi, B.; Jung, H.; Yu, B.; Choi, H.; Lee, J.; Kim, D.H. Sequential MR Image-Guided Local Immune Checkpoint Blockade Cancer Immunotherapy Using Ferumoxytol Capped Ultralarge Pore Mesoporous Silica Carriers after Standard Chemotherapy. Small 2019, 15, e1904378. [Google Scholar] [CrossRef]
  123. Mao, W.; Ghasemzadeh, A.; Freeman, Z.T.; Obradovic, A.; Chaimowitz, M.G.; Nirschl, T.R.; McKiernan, E.; Yegnasubramanian, S.; Drake, C.G. Immunogenicity of prostate cancer is augmented by BET bromodomain inhibition. J. Immunother. Cancer 2019, 7, 277. [Google Scholar] [CrossRef]
  124. Zhou, Q.; Xiong, W.; Zhou, X.; Gao, R.S.; Lin, Q.F.; Liu, H.Y.; Li, J.N.; Tian, X.F. CTHRC1 and PD-1/PD-L1 expression predicts tumor recurrence in prostate cancer. Mol. Med. Rep. 2019, 20, 4244–4252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Xu, Q.; Long, Q.; Zhu, D.; Fu, D.; Zhang, B.; Han, L.; Qian, M.; Guo, J.; Xu, J.; Cao, L.; et al. Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD-L1)-mediated immunosuppression. Aging Cell 2019, 18, e13027. [Google Scholar] [CrossRef] [Green Version]
  126. Dudzinski, S.O.; Cameron, B.D.; Wang, J.; Rathmell, J.C.; Giorgio, T.D.; Kirschner, A.N. Combination immunotherapy and radiotherapy causes an abscopal treatment response in a mouse model of castration resistant prostate cancer. J. Immunother. Cancer 2019, 7, 218. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Liu, K.; Zhou, Z.; Gao, H.; Yang, F.; Qian, Y.; Jin, H.; Guo, Y.; Liu, Y.; Li, H.; Zhang, C.; et al. JQ1, a BET-bromodomain inhibitor, inhibits human cancer growth and suppresses PD-L1 expression. Cell Biol. Int. 2019, 43, 642–650. [Google Scholar] [CrossRef]
  128. Xu, N.; Huang, L.; Li, X.; Watanabe, M.; Li, C.; Xu, A.; Liu, C.; Li, Q.; Araki, M.; Wada, K.; et al. The Novel Combination of Nitroxoline and PD-1 Blockade, Exerts a Potent Antitumor Effect in a Mouse Model of Prostate Cancer. Int. J. Biol. Sci. 2019, 15, 919–928. [Google Scholar] [CrossRef] [PubMed]
  129. Yoneda, T.; Kunimura, N.; Kitagawa, K.; Fukui, Y.; Saito, H.; Narikiyo, K.; Ishiko, M.; Otsuki, N.; Nibu, K.I.; Fujisawa, M.; et al. Overexpression of SOCS3 mediated by adenovirus vector in mouse and human castration-resistant prostate cancer cells increases the sensitivity to NK cells in vitro and in vivo. Cancer Gene Ther. 2019, 26, 388–399. [Google Scholar] [CrossRef]
  130. Fenerty, K.E.; Padget, M.; Wolfson, B.; Gameiro, S.R.; Su, Z.; Lee, J.H.; Rabizadeh, S.; Soon-Shiong, P.; Hodge, J.W. Immunotherapy utilizing the combination of natural killer- and antibody dependent cellular cytotoxicity (ADCC)-mediating agents with poly (ADP-ribose) polymerase (PARP) inhibition. J. Immunother. Cancer 2018, 6, 133. [Google Scholar] [CrossRef] [PubMed]
  131. Krueger, T.E.; Thorek, D.L.J.; Meeker, A.K.; Isaacs, J.T.; Brennen, W.N. Tumor-infiltrating mesenchymal stem cells: Drivers of the immunosuppressive tumor microenvironment in prostate cancer? Prostate 2019, 79, 320–330. [Google Scholar] [CrossRef] [PubMed]
  132. Medina Enríquez, M.M.; Félix, A.J.; Ciudad, C.J.; Noé, V. Cancer immunotherapy using PolyPurine Reverse Hoogsteen hairpins targeting the PD-1/PD-L1 pathway in human tumor cells. PLoS ONE 2018, 13, e0206818. [Google Scholar] [CrossRef] [PubMed]
  133. Moreira, D.; Adamus, T.; Zhao, X.; Su, Y.L.; Zhang, Z.; White, S.V.; Swiderski, P.; Lu, X.; DePinho, R.A.; Pal, S.K.; et al. STAT3 Inhibition Combined with CpG Immunostimulation Activates Antitumor Immunity to Eradicate Genetically Distinct Castration-Resistant Prostate Cancers. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2018, 24, 5948–5962. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Zhang, L.; Xu, L.J.; Zhu, J.; Li, J.; Xue, B.X.; Gao, J.; Sun, C.Y.; Zang, Y.C.; Zhou, Y.B.; Yang, D.R.; et al. ATM-JAK-PD-L1 signaling pathway inhibition decreases EMT and metastasis of androgen-independent prostate cancer. Mol. Med. Rep. 2018, 17, 7045–7054. [Google Scholar] [CrossRef] [Green Version]
  135. Yin, C.; Wang, Y.; Ji, J.; Cai, B.; Chen, H.; Yang, Z.; Wang, K.; Luo, C.; Zhang, W.; Yuan, C.; et al. Molecular Profiling of Pooled Circulating Tumor Cells from Prostate Cancer Patients Using a Dual-Antibody-Functionalized Microfluidic Device. Anal. Chem. 2018, 90, 3744–3751. [Google Scholar] [CrossRef] [PubMed]
  136. Ahern, E.; Harjunpää, H.; O’Donnell, J.S.; Allen, S.; Dougall, W.C.; Teng, M.W.L.; Smyth, M.J. RANKL blockade improves efficacy of PD1-PD-L1 blockade or dual PD1-PD-L1 and CTLA4 blockade in mouse models of cancer. Oncoimmunology 2018, 7, e1431088. [Google Scholar] [CrossRef] [Green Version]
  137. Xu, L.; Shen, M.; Chen, X.; Yang, D.R.; Tsai, Y.; Keng, P.C.; Lee, S.O.; Chen, Y. In vitro-induced M2 type macrophages induces the resistance of prostate cancer cells to cytotoxic action of NK cells. Exp. Cell Res. 2018, 364, 113–123. [Google Scholar] [CrossRef] [PubMed]
  138. Xu, L.; Chen, X.; Shen, M.; Yang, D.R.; Fang, L.; Weng, G.; Tsai, Y.; Keng, P.C.; Chen, Y.; Lee, S.O. Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell-mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels. Mol. Oncol. 2018, 12, 269–286. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  139. Xu, L.; Shen, M.; Chen, X.; Zhu, R.; Yang, D.R.; Tsai, Y.; Keng, P.C.; Chen, Y.; Lee, S.O. Adipocytes affect castration-resistant prostate cancer cells to develop the resistance to cytotoxic action of NK cells with alterations of PD-L1/NKG2D ligand levels in tumor cells. Prostate 2018, 78, 353–364. [Google Scholar] [CrossRef]
  140. Zhang, Y.; Zhu, S.; Qian, P.; Wang, X.; Xu, Z.; Sun, W.; Xu, Y. RelB upregulates PD-L1 in advanced prostate cancer: An insight into tumor immunoescape. Meeting Abstract 2791. Cancer Res. 2019, 79 (Suppl. S13), 2791. [Google Scholar]
  141. Shimizu, N.; De Velasco, M.A.; Kura, Y.; Sakai, K.; Sugimoto, K.; Nozawa, M.; Yoshimura, K.; Yoshikawa, K.; Nishio, K.; Uemura, H. PD-L1 immune checkpoint blockade in genetically engineered mouse models of prostate cancer. Cancer Sci. 2018, 109 (Suppl. S1), 292. [Google Scholar]
  142. Maher, C.M.; Thomas, J.D.; Haas, D.A.; Longen, C.G.; Oyer, H.M.; Tong, J.Y.; Kim, F.J. Small-Molecule Sigma1 Modulator Induces Autophagic Degradation of PD-L1. Mol. Cancer Res. 2018, 16, 243–255. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Shi, X.; Zhang, X.; Li, J.; Zhao, H.; Mo, L.; Shi, X.; Hu, Z.; Gao, J.; Tan, W. PD-1/PD-L1 blockade enhances the efficacy of SA-GM-CSF surface-modified tumor vaccine in prostate cancer. Cancer Lett. 2017, 406, 27–35. [Google Scholar] [CrossRef] [PubMed]
  144. Cappuccini, F.; Pollock, E.; Stribbling, S.; Hill, A.V.S.; Redchenko, I. 5T4 oncofoetal glycoprotein: An old target for a novel prostate cancer immunotherapy. Oncotarget 2017, 8, 47474–47489. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. De Velasco, M.A.; Kura, Y.; Ando, N.; Sato, N.; Sakai, K.; Davies, B.R.; Sugimoto, K.; Nozawa, M.; Yoshimura, K.; Yoshikawa, K.; et al. PD-L1 blockade in preclinical models of PTEN-deficient prostate cancer. Meeting Abstract: 4702. Cancer Res. 2017, 77 (Suppl. S13), 4702. [Google Scholar]
  146. Liu, Z.; Zhao, Y.; Fang, J.; Cui, R.; Xiao, Y.; Xu, Q. SHP2 negatively regulates HLA-ABC and PD-L1 expression via STAT1 phosphorylation in prostate cancer cells. Oncotarget 2017, 8, 53518–53530. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Tanoue, K.; Rosewell Shaw, A.; Watanabe, N.; Porter, C.; Rana, B.; Gottschalk, S.; Brenner, M.; Suzuki, M. Armed Oncolytic Adenovirus-Expressing PD-L1 Mini-Body Enhances Antitumor Effects of Chimeric Antigen Receptor T Cells in Solid Tumors. Cancer Res. 2017, 77, 2040–2051. [Google Scholar] [CrossRef] [Green Version]
  148. Wang, X.; Yang, L.; Huang, F.; Zhang, Q.; Liu, S.; Ma, L.; You, Z. Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells. Immunol. Lett. 2017, 184, 7–14. [Google Scholar] [CrossRef] [Green Version]
  149. Serganova, I.; Moroz, E.; Cohen, I.; Moroz, M.; Mane, M.; Zurita, J.; Shenker, L.; Ponomarev, V.; Blasberg, R. Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade. Mol. Ther. Oncolytics 2017, 4, 41–54. [Google Scholar] [CrossRef]
  150. Rekoske, B.T.; Olson, B.M.; McNeel, D.G. Antitumor vaccination of prostate cancer patients elicits PD-1/PD-L1 regulated antigen-specific immune responses. Oncoimmunology 2016, 5, e1165377. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  151. Rekoske, B.T.; Smith, H.A.; Olson, B.M.; Maricque, B.B.; McNeel, D.G. PD-1 or PD-L1 Blockade Restores Antitumor Efficacy Following SSX2 Epitope-Modified DNA Vaccine Immunization. Cancer Immunol. Res. 2015, 3, 946–955. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Black, M.; Barsoum, I.B.; Truesdell, P.; Cotechini, T.; Macdonald-Goodfellow, S.K.; Petroff, M.; Siemens, D.R.; Koti, M.; Craig, A.W.; Graham, C.H. Activation of the PD-1/PD-L1 immune checkpoint confers tumor cell chemoresistance associated with increased metastasis. Oncotarget 2016, 7, 10557–10567. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Yang, S.; Zhang, Q.; Liu, S.; Wang, A.R.; You, Z. PD-1, PD-L1 and PD-L2 expression in mouse prostate cancer. Am. J. Clin. Exp. Urol. 2016, 4, 1–8. [Google Scholar]
  154. Carbotti, G.; Barisione, G.; Airoldi, I.; Mezzanzanica, D.; Bagnoli, M.; Ferrero, S.; Petretto, A.; Fabbi, M.; Ferrini, S. IL-27 induces the expression of IDO and PD-L1 in human cancer cells. Oncotarget 2015, 6, 43267–43280. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Bernstein, M.B.; Garnett, C.T.; Zhang, H.; Velcich, A.; Wattenberg, M.M.; Gameiro, S.R.; Kalnicki, S.; Hodge, J.W.; Guha, C. Radiation-induced modulation of costimulatory and coinhibitory T-cell signaling molecules on human prostate carcinoma cells promotes productive antitumor immune interactions. Cancer Biother. Radiopharm. 2014, 29, 153–161. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. Yu, P.; Steel, J.C.; Zhang, M.; Morris, J.C.; Waitz, R.; Fasso, M.; Allison, J.P.; Waldmann, T.A. Simultaneous inhibition of two regulatory T-cell subsets enhanced Interleukin-15 efficacy in a prostate tumor model. Proc. Natl. Acad. Sci. USA 2012, 109, 6187–6192. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  157. Lin, H.; Liu, Q.; Zeng, X.; Yu, W.; Xu, G. Pembrolizumab with or without enzalutamide in selected populations of men with previously untreated metastatic castration-resistant prostate cancer harbouring programmed cell death ligand-1 staining: A retrospective study. BMC Cancer 2021, 21, 399. [Google Scholar] [CrossRef] [PubMed]
  158. Morel, K.L.; Sheahan, A.V.; Burkhart, D.L.; Baca, S.C.; Boufaied, N.; Liu, Y.; Qiu, X.; Cañadas, I.; Roehle, K.; Heckler, M.; et al. EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer. Nat. Cancer 2021, 2, 444–456. [Google Scholar] [CrossRef] [PubMed]
  159. Wu, Y.M.; Cieślik, M.; Lonigro, R.J.; Vats, P.; Reimers, M.A.; Cao, X.; Ning, Y.; Wang, L.; Kunju, L.P.; de Sarkar, N.; et al. Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer. Cell 2018, 173, 1770–1782.e14. [Google Scholar] [CrossRef] [Green Version]
  160. Rexer, H.; Graefen, M.; Merseburger, A.; AUO. Phase-II-Studie zu Pembrolizumab (MK-3475) bei Patienten mit metastasiertem kastrationsresistenten Prostatakarzinom (KEYNOTE-199)—Studie AP 93/16 der AUO Phase II study of pembrolizumab (MK-3475) in patients with metastatic castration-resistant prostate cancer (KEYNOTE-199)-study AP 93/16 of the AUO. Urol. A 2017, 56, 1471–1472. [Google Scholar]
  161. Calcinotto, A.; Spataro, C.; Zagato, E.; Di Mitri, D.; Gil, V.; Crespo, M.; Bernardis, G.; Losa, M.; Mirenda, M.; Pasquini, E.; et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature 2018, 559, 363–369. [Google Scholar] [CrossRef]
  162. Valente, M.J.; Henrique, R.; Costa, V.L.; Jeronimo, C.; Carvalho, F.; Bastos, M.L.; de Pinho, P.G.; Carvalho, M. A rapid and simple procedure for the establishment of human normal and cancer renal primary cell cultures from surgical specimens. PLoS ONE 2011, 6, e19337. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Wang, Y.; Jadhav, R.R.; Liu, J.; Wilson, D.; Chen, Y.; Thompson, I.M.; Troyer, D.A.; Hernandez, J.; Shi, H.; Leach, R.J.; et al. Roles of distal and genic methylation in the development of prostate tumori-genesis revealed by genome-wide DNA methylation analysis. Sci. Rep. 2016, 6, 22051. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  164. Macedo-Silva, C.; Benedetti, R.; Ciardiello, F.; Cappabianca, S.; Jerónimo, C.; Altucci, L. Epigenetic mechanisms underlying prostate cancer radioresistance. Clin. Epigenetics 2021, 13, 125. [Google Scholar] [CrossRef] [PubMed]
  165. Chen, T.; Li, E. Structure and function of eukaryotic DNA methyltransferases. Curr. Top. Dev. Biol. 2014, 60, 55–89. [Google Scholar]
  166. Subramaniam, D.; Thombre, R.; Dhar, A.; Anant, S. DNA methyltransferases: A novel target for prevention and therapy. Front. Oncol. 2014, 4, 80. [Google Scholar] [CrossRef] [PubMed]
  167. Li, F.; Papworth, M.; Minczuk, M.; Rohde, C.; Zhang, Y.; Ragozin, S.; Jeltsch, A. Chimeric DNA methyltransferases target DNA methylation to specific DNA sequences and repress expression of target genes. Nucleic Acids Res. 2007, 35, 100–112. [Google Scholar] [CrossRef] [Green Version]
  168. Zlotnik, A. New insights on the role of CXCR4 in cancer metastasis. J. Pathol. 2008, 215, 211–213. [Google Scholar] [CrossRef]
  169. Hsiao, J.J.; Ng, B.H.; Smits, M.M.; Wang, J.; Jasavala, R.J.; Martinez, H.D.; Lee, J.; Alston, J.J.; Misonou, H.; Trimmer, J.S.; et al. Androgen receptor and chemokine receptors 4 and 7 form a signaling axis to regulate CXCL12-dependent cellular motility. BMC Cancer 2015, 15, 204. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  170. Fearon, D.T. The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol. Res. 2014, 2, 187–193. [Google Scholar] [CrossRef] [Green Version]
  171. Scala, S. Molecular Pathways: Targeting the CXCR4–CXCL12 Axis-Untapped Potential in the Tumor Microenvironment. Clin Cancer Res. 2015, 21, 4278–4285. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  172. Li, Y.; Seto, E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb. Perspect. Med. 2016, 6, a026831. [Google Scholar] [CrossRef] [Green Version]
  173. Kaushik, D.; Vashistha, V.; Isharwal, S.; Sediqe, S.A.; Lin, M.F. Histone deacetylase inhibitors in castration-resistant prostate cancer: Molecular mechanism of action and recent clinical trials. Ther. Adv. Urol. 2015, 7, 388–395. [Google Scholar] [CrossRef] [Green Version]
  174. Zhong, J.; Ding, L.; Bohrer, L.R.; Pan, Y.; Liu, P.; Zhang, J.; Sebo, T.J.; Karnes, R.J.; Tindall, D.J.; van Deursen, J.; et al. p300 acetyltransferase regulates androgen receptor degradation and PTEN-deficient prostate tumorigenesis. Cancer Res. 2014, 74, 1870–1880. [Google Scholar] [CrossRef] [Green Version]
  175. Lasko, L.M.; Jakob, C.G.; Edalji, R.P.; Qiu, W.; Montgomery, D.; Digiammarino, E.L.; Hansen, T.M.; Risi, R.M.; Frey, R.; Manaves, V.; et al. Discovery of a selective catalytic p300/ CBP inhibitor that targets lineage-specific tumours. Nature 2017, 550, 128–132. [Google Scholar] [CrossRef] [PubMed]
  176. Eckschlager, T.; Plch, J.; Stiborova, M.; Hrabeta, J. Histone deacetylase inhibitors as anticancer drugs. Int. J. Mol. Sci. 2017, 18, 1414. [Google Scholar] [CrossRef] [PubMed]
  177. Tumes, D.J.; Onodera, A.; Suzuki, A.; Shinoda, K.; Endo, Y.; Iwamura, C.; Hosokawa, H.; Koseki, H.; Tokoyoda, K.; Suzuki, Y.; et al. The polycomb protein Ezh2 regulates diferentiation and plasticity of CD4+ T helper type 1 and type 2 cells. Immunity 2013, 39, 819–832. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  178. Soshnev, A.A.; Josefowicz, S.Z.; Allis, C.D. Greater than the sum of parts: Complexity of the dynamic epigenome. Mol. Cell 2018, 69, 533. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  179. Goswami, S.; Apostolou, I.; Zhang, J.; Skepner, J.; Anandhan, S.; Zhang, X.; Xiong, L.; Trojer, P.; Aparicio, A.; Subudhi, S.K.; et al. Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy. J. Clin. Investig. 2018, 128, 3813–3818. [Google Scholar] [CrossRef] [PubMed]
  180. Dai, X.; Gan, W.; Li, X.; Wang, S.; Zhang, W.; Huang, L.; Liu, S.; Zhong, Q.; Guo, J.; Zhang, J.; et al. Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nat. Med. 2017, 23, 1063–1071. [Google Scholar] [CrossRef] [Green Version]
  181. Jang, M.K.; Mochizuki, K.; Zhou, M.; Jeong, H.S.; Brady, J.N.; Ozato, K. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol. Cell 2005, 19, 523–534. [Google Scholar] [CrossRef] [PubMed]
  182. Antonarakis, E.S.; Chandhasin, C.; Osbourne, E.; Luo, J.; Sadar, M.D.; Perabo, F. Targeting the N-Terminal Domain of the Androgen Receptor: A New Approach for the Treatment of Advanced Prostate Cancer. Oncologist 2016, 21, 1427–1435. [Google Scholar] [CrossRef] [Green Version]
  183. Delmore, J.E.; Issa, G.C.; Lemieux, M.E.; Rahl, P.B.; Shi, J.; Jacobs, H.M.; Kastritis, E.; Gilpatrick, T.; Paranal, R.M.; Qi, J.; et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011, 146, 904–917. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  184. Liang, C.; Wang, S.; Qin, C.; Bao, M.; Cheng, G.; Liu, B.; Shao, P.; Lv, Q.; Song, N.; Hua, L.; et al. TRIM36, a novel androgen-responsive gene, enhances anti-androgen efficacy against prostate cancer by inhibiting MAPK/ERK signaling pathways. Cell Death Dis. 2018, 9, 155. [Google Scholar] [CrossRef] [PubMed]
  185. Zhang, D.; Tian, J.; Roden, C.; Lu, J. Post-transcriptional Regulation is the Major Driver of microRNA Expression Variation. bioRxiv 2020. [Google Scholar] [CrossRef]
  186. Wu, D.; Li, Y.; Zhang, H.; Hu, X. Knockdown of Lncrna PVT1 Enhances Radiosensitivity in Non-Small Cell Lung Cancer by Sponging Mir-195. Cell Physiol. Biochem. 2017, 42, 2453–2466. [Google Scholar] [CrossRef] [PubMed]
  187. Lan, F.; Yue, X.; Ren, G.; Li, H.; Ping, L.; Wang, Y.; Xia, T. miR-15a/16 enhances radiation sensitivity of non-small cell lung cancer cells by targeting the TLR1/NF-kappaB signaling pathway. Int. J. Radiat. Oncol. Biol. Phys. 2015, 91, 73–81. [Google Scholar] [CrossRef] [PubMed]
  188. Cai, C.; Chen, Q.B.; Han, Z.D.; Zhang, Y.Q.; He, H.C.; Chen, J.H. miR-195 Inhibits Tumor Progression by Targeting RPS6KB1 in Human Prostate Cancer. Clin. Cancer Res. 2015, 21, 4922–4934. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  189. Bonci, D.; Coppola, V.; Musumeci, M.; Addario, A.; Giuffrida, R.; Memeo, L.; D’Urso, L.; Pagliuca, A.; Biffoni, M.; Labbaye, C.; et al. The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat. Med. 2008, 14, 1271–1277. [Google Scholar] [CrossRef] [PubMed]
  190. Jin, W.; Chen, F.; Wang, K.; Song, Y.; Fei, X.; Wu, B. miR-15a/miR-16 cluster inhibits invasion of prostate cancer cells by suppressing TGF-beta signaling pathway. Biomed. Pharmacother. 2018, 104, 637–644. [Google Scholar] [CrossRef]
  191. Aqeilan, R.I.; Calin, G.A.; Croce, C.M. miR-15a and miR-16-1 in cancer: Discovery, function and future perspectives. Cell Death Differ. 2010, 17, 215–220. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  192. Liu, T.; Xu, Z.; Ou, D.; Liu, J.; Zhang, J. The miR-15a/16 gene cluster in human cancer: A systematic review. J. Cell Physiol. 2019, 234, 5496–5506. [Google Scholar] [CrossRef]
  193. Kao, S.C.; Cheng, Y.Y.; Williams, M.; Kirschner, M.B.; Madore, J.; Lum, T.; Sarun, K.H.; Linton, A.; McCaughan, B.; Klebe, S.; et al. Tumor suppressor microRNAs contribute to the regulation of PD-L1 expression in malignant pleural mesothelioma. J. Thorac. Oncol. 2017, 12, 1421–1433. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  194. Hsu, T.I.; Wang, Y.C.; Hung, C.Y.; Yu, C.H.; Su, W.C.; Chang, W.C.; Hung, J.J. Positive feedback regulation between IL10 and EGFR promotes lung cancer formation. Oncotarget 2016, 7, 20840–20854. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  195. Coelho, M.A.; de Carne Trecesson, S.; Rana, S.; Zecchin, D.; Moore, C.; Molina-Arcas, M.; East, P.; Spencer-Dene, B.; Nye, E.; Barnouin, K.; et al. Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA. Immunity 2017, 47, 1083–1099. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  196. Sumimoto, H.; Takano, A.; Teramoto, K.; Daigo, Y. RAS-mitogen-activated protein kinase signal is required for enhanced PD-L1 expression in human lung cancers. PLoS ONE 2016, 11, e0166626. [Google Scholar] [CrossRef] [PubMed]
  197. Ju, G.; Zhu, Y.; Du, T.; Cao, W.; Lin, J.; Li, C.; Xu, D.; Wang, Z. MiR-197 Inhibitor Loaded AbCD133@MSNs@GNR Affects the Development of Prostate Cancer Through Targeting ITGAV. Front. Cell Dev. Biol. 2021, 9, 646884. [Google Scholar] [CrossRef]
  198. Zhu, J.; Wang, S.; Zhang, W.; Qiu, J.; Shan, Y.; Yang, D.; Shen, B. Screening key microRNAs for castration-resistant prostate cancer based on miRNA/mRNA functional synergistic network. Oncotarget 2015, 6, 43819–43830. [Google Scholar] [CrossRef]
  199. Huang, Q.; Ma, B.; Su, Y.; Chan, K.; Qu, H.; Huang, J.; Wang, D.; Qiu, J.; Liu, H.; Yang, X.; et al. miR-197-3p Represses the Proliferation of Prostate Cancer by Regulating the VDAC1/AKT/β-catenin Signaling Axis. Int. J. Biol. Sci. 2020, 16, 1417–1426. [Google Scholar] [CrossRef] [PubMed]
  200. Yuan, Y.; Chen, X.; Huang, E. Upregulation of Circular RNA Itchy E3 Ubiquitin Protein Ligase Inhibits Cell Proliferation and Promotes Cell Apoptosis Through Targeting MiR-197 in Prostate Cancer. Technol. Cancer Res. Treat. 2019, 18, 1533033819886867. [Google Scholar] [CrossRef]
  201. Fletcher, C.E.; Sulpice, E.; Combe, S.; Shibakawa, A.; Leach, D.A.; Hamilton, M.P.; Chrysostomou, S.L.; Sharp, A.; Welti, J.; Yuan, W.; et al. Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer. Oncogene 2019, 38, 5700–5724. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  202. Abisoye-Ogunniyan, A.; Lin, H.; Ghebremedhin, A.; Salam, A.B.; Karanam, B.; Theodore, S.; Jones-Trich, J.; Davis, M.; Grizzle, W.; Wang, H.; et al. Transcriptional repressor Kaiso promotes epithelial to mesenchymal transition and metastasis in prostate cancer through direct regulation of miR-200c. Cancer Lett. 2018, 431, 1–10. [Google Scholar] [CrossRef]
  203. Kong, D.; Li, Y.; Wang, Z.; Banerjee, S.; Ahmad, A.; Kim, H.R.; Sarkar, F.H. miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells. Stem. Cells 2009, 27, 1712–1721. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  204. Williams, L.V.; Veliceasa, D.; Vinokour, E.; Volpert, O.V. miR-200b inhibits prostate cancer EMT, growth and metastasis. PLoS ONE 2013, 8, e83991. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  205. Verma, S.; Pandey, M.; Shukla, G.C.; Singh, V.; Gupta, S. Integrated analysis of miRNA landscape and cellular networking pathways in stage-specific prostate cancer. PLoS ONE 2019, 14, e0224071. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  206. Zhang, Z.; Lanz, R.B.; Xiao, L.; Wang, L.; Hartig, S.M.; Ittmann, M.M.; Feng, Q.; He, B. The tumor suppressive miR-200b subfamily is an ERG target gene in human prostate tumors. Oncotarget 2016, 7, 37993–38003. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  207. Barron, N.; Keenan, J.; Gammell, P.; Martinez, V.G.; Freeman, A.; Masters, J.R.; Clynes, M. Biochemical relapse following radical prostatectomy and miR-200a levels in prostate cancer. Prostate 2012, 72, 1193–1199. [Google Scholar] [CrossRef] [PubMed]
  208. Pang, Y.; Young, C.Y.; Yuan, H. MicroRNAs and prostate cancer. Acta Biochim. Biophys. Sin. 2010, 42, 363–369. [Google Scholar] [CrossRef] [Green Version]
  209. Kopczyńska, E. Role of microRNAs in the resistance of prostate cancer to docetaxel and paclitaxel. Contemp. Oncol. 2015, 19, 423–427. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  210. Dallavalle, C.; Albino, D.; Civenni, G.; Merulla, J.; Ostano, P.; Mello-Grand, M.; Rossi, S.; Losa, M.; D’Ambrosio, G.; Sessa, F.; et al. MicroRNA-424 impairs ubiquitination to activate STAT3 and promote prostate tumor progression. J. Clin. Investig. 2016, 126, 4585–4602. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  211. Banyard, J.; Chung, I.; Wilson, A.M.; Vetter, G.; Le Béchec, A.; Bielenberg, D.R.; Zetter, B.R. Regulation of epithelial plasticity by miR-424 and miR-200 in a new prostate cancer metastasis model. Sci. Rep. 2013, 3, 3151. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  212. Stuopelytê, K.; Daniūnaitė, K.; Jankevičius, F.; Jarmalaitė, S. Detection of miRNAs in urine of prostate cancer patients. Medicinae 2016, 52, 116–124. [Google Scholar] [CrossRef]
  213. Kim, W.T.; Kim, W.J. MicroRNAs in prostate cancer. Prostate Int. 2013, 1, 3–9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  214. Albino, D.; Falcione, M.; Uboldi, V.; Temilola, D.O.; Sandrini, G.; Merulla, J.; Civenni, G.; Kokanovic, A.; Stürchler, A.; Shinde, D.; et al. Circulating extracellular vesicles release oncogenic miR-424 in experimental models and patients with aggressive prostate cancer. Commun. Biol. 2021, 4, 119. [Google Scholar] [CrossRef] [PubMed]
  215. Young, C.; Horton, R. Putting clinical trials into context. Lancet 2005, 366, 107–108. [Google Scholar] [CrossRef]
  216. Palicelli, A.; Giaccherini, L.; Zanelli, M.; Bonasoni, M.P.; Gelli, M.C.; Bisagni, A.; Zanetti, E.; De Marco, L.; Torricelli, F.; Manzotti, G.; et al. How Can We Treat Vulvar Carcinoma in Pregnancy? A Systematic Review of the Literature. Cancers 2021, 13, 836. [Google Scholar] [CrossRef] [PubMed]
  217. Wing-Cheuk Wong, R.; Palicelli, A.; Hoang, L.; Singh, N. Interpretation of p16, p53 and mismatch repair protein immunohistochemistry in gynaecological neoplasia. Diagn. Histopathol. 2020, 26, 257–277. [Google Scholar] [CrossRef]
  218. Sanguedolce, F.; Calò, B.; Mancini, V.; Zanelli, M.; Palicelli, A.; Zizzo, M.; Ascani, S.; Carrieri, G.; Cormio, L. Non-Muscle Invasive Bladder Cancer with Variant Histology: Biological Features and Clinical Implications. Oncology 2021, 99, 345–358. [Google Scholar] [CrossRef]
  219. Zanelli, M.; Sanguedolce, F.; Zizzo, M.; Palicelli, A.; Bassi, M.C.; Santandrea, G.; Martino, G.; Soriano, A.; Caprera, C.; Corsi, M.; et al. Primary effusion lymphoma occurring in the setting of transplanted patients: A systematic review of a rare, life-threatening post-transplantation occurrence. BMC Cancer 2021, 21, 468. [Google Scholar] [CrossRef]
  220. De Leo, A.; Santini, D.; Ceccarelli, C.; Santandrea, G.; Palicelli, A.; Acquaviva, G.; Chiarucci, F.; Rosini, F.; Ravegnini, G.; Pession, A.; et al. What Is New on Ovarian Carcinoma: Integrated Morphologic and Molecular Analysis Following the New 2020 World Health Organization Classification of Female Genital Tumors. Diagnostics 2021, 11, 697. [Google Scholar] [CrossRef]
  221. Foda, A.A.; Palicelli, A.; Shebl, A.; Boldorini, R.; Elnaghi, K.; ElHawary, A.K. Role of ERCC1 expression in colorectal adenoma-carcinoma sequence and relation to other mismatch repair proteins expression, clinicopathological features and prognosis in mucinous and non-mucinous colorectal carcinoma. Indian J. Pathol. Microbiol. 2019, 62, 405–412. [Google Scholar] [CrossRef]
  222. Sanguedolce, F.; Zanelli, M.; Zizzo, M.; Bisagni, A.; Soriano, A.; Cocco, G.; Palicelli, A.; Santandrea, G.; Caprera, C.; Corsi, M.; et al. Primary Pulmonary B-Cell Lymphoma: A Review and Update. Cancers 2021, 13, 415. [Google Scholar] [CrossRef]
  223. Bonasoni, M.P.; Palicelli, A.; Dalla Dea, G.; Comitini, G.; Pazzola, G.; Russello, G.; Bertoldi, G.; Bardaro, M.; Zuelli, C.; Carretto, E. Kingella kingae Intrauterine Infection: An Unusual Cause of Chorioamnionitis and Miscarriage in a Patient with Undifferentiated Connective Tissue Disease. Diagnostics 2021, 11, 243. [Google Scholar] [CrossRef]
  224. Bonasoni, M.P.; Palicelli, A.; Dalla Dea, G.; Comitini, G.; Nardini, P.; Vizzini, L.; Russello, G.; Bardaro, M.; Carretto, E. Klebsiella pneumoniae Chorioamnionitis: An Underrecognized Cause of Preterm Premature Rupture of Membranes in the Second Trimester. Microorganisms 2021, 9, 96. [Google Scholar] [CrossRef]
  225. Olivadese, R.; Ramponi, A.; Boldorini, R.; Dalla Dea, G.; Palicelli, A. Mitotically Active Cellular Fibroma of the Ovary Recurring After the Longest Interval of Time (16 yr): A Challenging Case with Systematic Literature Review. Int. J. Gynecol. Pathol. 2021, 40, 441–447. [Google Scholar] [CrossRef]
  226. Zanelli, M.; Ricci, S.; Zizzo, M.; Sanguedolce, F.; De Giorgi, F.; Palicelli, A.; Martino, G.; Ascani, S. Systemic Mastocytosis Associated with “Smoldering” Multiple Myeloma. Diagnostics 2021, 11, 88. [Google Scholar] [CrossRef] [PubMed]
  227. Palicelli, A. What do we know about the cytological features of pure intraductal carcinomas of the salivary glands? Cytopathology 2020, 31, 185–192. [Google Scholar] [CrossRef] [PubMed]
  228. Palicelli, A. Intraductal carcinomas of the salivary glands: Systematic review and classification of 93 published cases. APMIS 2020, 128, 191–200. [Google Scholar] [CrossRef] [PubMed]
  229. Ardighieri, L.; Palicelli, A.; Ferrari, F.; Bugatti, M.; Drera, E.; Sartori, E.; Odicino, F. Endometrial Carcinomas with Intestinal-Type Metaplasia/Differentiation: Does Mismatch Repair System Defects Matter? Case Report and Systematic Review of the Literature. J. Clin. Med. 2020, 9, 2552. [Google Scholar] [CrossRef] [PubMed]
  230. D’Agostino, C.; Surico, D.; Monga, G.; Palicelli, A. Pregnancy-related decidualization of subcutaneous endometriosis occurring in a post-caesarean section scar: Case study and review of the literature. Pathol. Res. Pract. 2019, 215, 828–831. [Google Scholar] [CrossRef] [PubMed]
  231. Palicelli, A.; Barbieri, P.; Mariani, N.; Re, P.; Galla, S.; Sorrentino, R.; Locatelli, F.; Salfi, N.; Valente, G. Unicystic high-grade intraductal carcinoma of the parotid gland: Cytological and histological description with clinic-pathologic review of the literature. APMIS 2018, 126, 771–776. [Google Scholar] [CrossRef] [PubMed]
  232. Palicelli, A.; Neri, P.; Marchioro, G.; De Angelis, P.; Bondonno, G.; Ramponi, A. Paratesticular seminoma: Echographic features and histological diagnosis with review of the literature. APMIS 2018, 126, 267–272. [Google Scholar] [CrossRef] [PubMed]
  233. Disanto, M.G.; Mercalli, F.; Palicelli, A.; Arnulfo, A.; Boldorini, R. A unique case of bilateral ovarian splenosis and review of the literature. APMIS 2017, 125, 844–848. [Google Scholar] [CrossRef] [PubMed]
  234. Palicelli, A.; Disanto, M.G.; Panzarasa, G.; Veggiani, C.; Galizia, G.; Dal Cin, S.; Gruppioni, E.; Boldorini, R. Orbital meningeal melanocytoma: Histological, immunohistochemical and molecular characterization of a case and review of the literature. Pathol. Res. Pract. 2016, 212, 946–953. [Google Scholar] [CrossRef]
  235. Zanelli, M.; Smith, M.; Zizzo, M.; Carloni, A.; Valli, R.; De Marco, L.; Foroni, M.; Palicelli, A.; Martino, G.; Ascani, S. A tricky and rare cause of pulmonary eosinophilia: Myeloid/lymphoid neoplasm with eosinophilia and rearrangement of PDGFRA. BMC Pulm. Med. 2019, 19, 216. [Google Scholar] [CrossRef]
  236. Palicelli, A.; Boldorini, R.; Campisi, P.; Disanto, M.G.; Gatti, L.; Portigliotti, L.; Tosoni, A.; Rivasi, F. Tungiasis in Italy: An imported case of Tunga penetrans and review of the literature. Pathol. Res. Pract. 2016, 212, 475–483. [Google Scholar] [CrossRef] [PubMed]
  237. Ambrosetti, F.; Palicelli, A.; Bulfamante, G.; Rivasi, F. Langer mesomelic dysplasia in early fetuses: Two cases and a literature review. Fetal. Pediatr. Pathol. 2014, 33, 71–83. [Google Scholar] [CrossRef] [PubMed]
  238. Mandato, V.D.; Mastrofilippo, V.; Palicelli, A.; Silvotti, M.; Serra, S.; Giaccherini, L.; Aguzzoli, L. Solitary vulvar metastasis from early-stage endometrial cancer: Case report and literature review. Medicine 2021, 100, e25863. [Google Scholar] [CrossRef] [PubMed]
  239. Ardighieri, L.; Palicelli, A.; Ferrari, F.; Ragnoli, M.; Ghini, I.; Bugatti, M.; Bercich, L.; Sartori, E.; Odicino, F.E. Risk Assessment in Solitary Fibrous Tumor of the Uterine Corpus: Report of a Case and Systematic Review of the Literature. Int. J. Surg. Pathol. 2021, 28, 10668969211025759. [Google Scholar] [CrossRef] [PubMed]
  240. Zanelli, M.; Pizzi, M.; Sanguedolce, F.; Zizzo, M.; Palicelli, A.; Soriano, A.; Bisagni, A.; Martino, G.; Caprera, C.; Moretti, M.; et al. Gastrointestinal Manifestations in Systemic Mastocytosis: The Need of a Multidisciplinary Approach. Cancers 2021, 13, 3316. [Google Scholar] [CrossRef]
  241. Donegani, E.; Ambassa, J.C.; Mvondo, C.; Giamberti, A.; Ramponi, A.; Palicelli, A.; Chelo, D. Linfoma di Burkitt cardiaco primitivo in un giovane ragazzo africano. Primary cardiac Burkitt lymphoma in an African child. Giornale Ital. Cardiol. 2013, 14, 481–484. [Google Scholar]
  242. Zanelli, M.; Ragazzi, M.; Marchetti, G.; Bisagni, A.; Principi, M.; Fanni, D.; Froio, E.; Serra, S.; Zanetti, E.; De Marco, L.; et al. Primary histiocytic sarcoma presenting as diffuse leptomeningeal disease: Case description and review of the literature. Neuropathology 2017, 37, 517–525. [Google Scholar] [CrossRef] [PubMed]
  243. Minni, F.; Casadei, R.; Santini, D.; Verdirame, F.; Zanelli, M.; Vesce, G.; Marrano, D. Gastrointestinal autonomic nerve tumor of the jejunum. Case report and review of the literature. Ital. J. Gastroenterol. Hepatol. 1997, 6, 558–563. [Google Scholar]
  244. Zizzo, M.; Ugoletti, L.; Manzini, L.; Castro Ruiz, C.; Nita, G.E.; Zanelli, M.; De Marco, L.; Besutti, G.; Scalzone, R.; Sassatelli, R.; et al. Management of duodenal stump fistula after gastrectomy for malignant disease: A systematic review of the literature. BMC Surg. 2019, 19, 55. [Google Scholar]
  245. Bonasoni, M.P.; Comitini, G.; Barbieri, V.; Palicelli, A.; Salfi, N.; Pilu, G. Fetal Presentation of Mediastinal Immature Teratoma: Ultrasound, Autopsy and Cytogenetic Findings. Diagnostics 2021, 11, 1543. [Google Scholar] [CrossRef] [PubMed]
  246. Zanelli, M.; Sanguedolce, F.; Palicelli, A.; Zizzo, M.; Martino, G.; Caprera, C.; Fragliasso, V.; Soriano, A.; Valle, L.; Ricci, S.; et al. EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 1). Cancers 2021, 13, 4578. [Google Scholar] [CrossRef] [PubMed]
  247. Zanelli, M.; Sanguedolce, F.; Palicelli, A.; Zizzo, M.; Martino, G.; Caprera, C.; Fragliasso, V.; Soriano, A.; Valle, L.; Ricci, S.; et al. EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 2). Cancers 2021, 13, 4527. [Google Scholar] [CrossRef]
  248. Sanguedolce, F.; Zanelli, M.; Zizzo, M.; Luminari, S.; Martino, G.; Soriano, A.; Ricci, L.; Caprera, C.; Ascani, S. Indolent T-cell lymphoproliferative disorders of the gastrointestinal tract (iTLPD-GI): A review. Cancers 2021, 13, 2790. [Google Scholar] [CrossRef]
  249. Zanelli, M.; Mengoli, M.C.; Del Sordo, R.; Cagini, A.; De Marco, L.; Simonetti, E.; Martino, G.; Zizzo, M.; Ascani, S. Intravascular NK/T-cell lymphoma, Epstein-Barr virus positive with multiorgan involvement: A clinical dilemma. BMC Cancer 2018, 18, 1115. [Google Scholar] [CrossRef]
  250. Palicelli, A.; Bonacini, M.; Croci, S.; Magi-Galluzzi, C.; Cañete-Portillo, S.; Chaux, A.; Bisagni, A.; Zanetti, E.; De Biase, D.; Melli, B.; et al. What do we have to know about PD-L1 expression in prostate cancer? A systematic literature review. Part 1: Focus on immunohistochemical results with discussion of pre-analytical and interpretation variables. Cells 2021, 10, 3166. [Google Scholar] [CrossRef]
  251. Palicelli, A.; Bonacini, M.; Croci, S.; Magi-Galluzzi, C.; Cañete-Portillo, S.; Chaux, A.; Bisagni, A.; Zanetti, E.; De Biase, D.; Melli, B.; et al. What do we have to know about PD-L1 expression in prostate cancer? A systematic literature review. Part 2: Clinic-pathologic correlations. Cells 2021, 10, 3165. [Google Scholar] [CrossRef]
  252. Palicelli, A.; Croci, S.; Bisagni, A.; Zanetti, E.; De Biase, D.; Melli, B.; Sanguedolce, F.; Ragazzi, M.; Zanelli, M.; Chaux, A.; et al. What do we have to know about PD-L1 expression in prostate cancer? A systematic literature review. Part 3: PD-L1, intracellular signaling pathways and tumor microenvironment. Int. J. Mol. Sci. 2021, 22, 12330. [Google Scholar]
  253. Palicelli, A.; Croci, S.; Bisagni, A.; Zanetti, E.; De Biase, D.; Melli, B.; Sanguedolce, F.; Ragazzi, M.; Zanelli, M.; Chaux, A.; et al. What do we have to know about PD-L1 expression in prostate cancer? A systematic literature review. Part 4: Experimental treatments in pre-clinical studies (cell lines and mouse models). Int. J. Mol. Sci. 2021, 22, 12297. [Google Scholar] [CrossRef]
Figure 1. Review of the literature: PRISMA flow-chart.
Figure 1. Review of the literature: PRISMA flow-chart.
Ijms 22 12314 g001
Table 1. PD-L1 epigenetic regulation in prostatic carcinoma-derived cell lines.
Table 1. PD-L1 epigenetic regulation in prostatic carcinoma-derived cell lines.
Experiment TypeCell LinesEffects on PD-L1 ExpressionPossible Mechanism of Action
DNMTDnmt1, Dnmt3 [7]Methyltransferase overexpressionDU145NegNR
Histone modifiersMLL3 [60]MLL3 deletionPC3, TRAMP-C2PosNR
MML1 [14]MLL1 silencingPC3, DU145PosNR
HDAC class I [116]HDAC class I deletionDU145NegNR
p300/CBP [116]EP300 or CBP deletionDU145PosNR
miRNAsmiR-195, miR-16 [73]miRNA overexpressionPC3, DU145, TRAMP-C1NegNR
miR-15 [26]Co with TTC with miRNA mimic or inhibitorPC3, DU145 (*)NegReduction of cell viability, migration and invasion, and increased apoptosis of tumor cells. Increased CD8+ T cell cytotoxicity when miR-15 is overexpressed. Opposite effects when miR-15 is inhibited.
Long non-coding RNAKCNQ1OT1 [26]Co with long non-coding RNA overexpressed TTCPC3, DU145 (*)PosIncreased cell viability, migration, invasion and apoptosis of tumor cells, reduction of CD8+ T cell cytotoxicity.
mRNA translation modulatorseEF2K [159]eEF2K ablationPC3PoseEF2K promotes the association of PD-L1 mRNAs with translationally active polyribosomes, enhancing PD-L1 expression. eEF2K-depleted cancer cells are more vulnerable to NK cells.
(*): effects on CD8+ T-cell infiltrate were also investigated. Co: Co-culture; DNMT: DNA methyltransferase; HDAC: Histone deacetylase; Neg: Negative regulator; NR: not reported (no effect was investigated); Pos: Positive regulator; TTC: transfected tumor cells.
Table 2. Experimental treatments with epigenetic drugs.
Table 2. Experimental treatments with epigenetic drugs.
DrugDrug TypeExperiment TypeCell LinesEffects on PD-L1Studied Effect
JQ1 [127]bromodomain inhibitorTreatmentPC3↓ Proliferation
JQ1 [123]bromodomain inhibitorTreatmentPC3, DU145, Myc-CapNEI
RVX [123]bromodomain inhibitorTreatmentPC3NEI
SAHA [116]HDAC class I-II inhibitorTreatmentPC3, DU145NEI
LBH589 [116]pan-deacetylase inhibitorTreatmentPC3, DU145NEI
A485 [116]p300/CBP inhibitorTreatmentTRAMP-C2 RasNEI
OIRC-9429 [14]WDR5 inhibitorTreatmentPC3, DU145NEI
EZH2 inhibitor [158]EZH2 inhibitorTreatmentMYC-CaP↑ genes involved in antigen presentation, Th1 chemokine signaling and IFN response
↑ CD8+ and CD4+ T cells
↓ Tregs
↑ M1 TAMs
↓ M2 TAMs
↓ Downregulation or decrease; ↑ Upregulation or increase; IFN: interferon; NEI: No effect was investigated; TAMs: tumor-associated macrophages; Tregs: regulatory T cells.
Table 3. Epigenetic regulation of PD-L1: human studies on prostatic adenocarcinoma.
Table 3. Epigenetic regulation of PD-L1: human studies on prostatic adenocarcinoma.
Ref.SamplesGG/StageResults
[26]30 PC
30 BPT
NRInverse correlation between PD-L1 and miR-15a levels. Significantly higher KCNQ1OT1, PD-L1, and CD8 expression in PCs than BPT (lower miR-15a levels).
[60]66 mCRPC (RP, MTS)GG: 1–5
Stage: I–IV
MLL3 and PD-L1 RNA levels positively correlated to PSA (not GG, age or stage). In 23 paired castration-resistant PC samples, higher MLL3 and PD-L1 RNA levels in MTS than in primary PC samples.
[73]40 PC (ff)
20 BPT (ff)
NRmiR-195 and miR-16 expression inversely correlated to PD-L1 levels in PC.
High miR-195/miR-16 levels correlated to longer BRFS.
[90,93]TC: 498 PC (TCGA);
VC: 299 PC (RP)
GG: 1–5
Stage: pT2–4 Nx/0/1
Lower levels of mPD-L1 in normal prostate (vs. PC). On multivariate analysis, mPD-L1high (HR = 1.22 [95%CI: 1.05–1.42] p = 0.008) and pePD-L1high (HR = 2.58, 95% CI: 1.43–4.63; p = 0.002) (analyzed as continuous variables) correlated to shorter BRFS (vs. pePD-L1low/mPD-L1low) in TC (not in VC). pePD-L1high/mPD-L1low or pePD-L1low/mPD-L1high showed intermediate BRFS. mPD-L1 corelated to pT stage (p = 0.010) and GG (p = 0.001). miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to mPD-L1 (possible association of mPD-L1 with decreased mRNA levels destabilizing miR-197 and miR-200a-c). miR-570 correlated to mPD-L1. miR-34a inversely correlated to mPD-L1 and mRNA expression. Trend toward an association of PD-L1 with mCXCL12 (Spearman’s rank correlation; ρ = 0.132, p = 0.084). Kaplan–Meier analysis: PD-L1low PCs (n = 85) showed the longest BRFS (mean 112 months), PD-L1high/mCXCL12medium PCs (n = 45) had the best BRFS (mean 107 months), PD-L1high/mCXCL12low (n = 15) and PD-L1high/mCXCL12high (n = 27) PCs showed short BRFS (mean 52 and 83 months, respectively; n = 151, χ2 = 12.99; p = 0.005).
[116]495 (TCGA)NREP300 (p300), CREBBP (CBP), KAT2B (PCAF), and BRD4 positively correlated to CD274 expression (p < 0.001) (comparable with IRF-1). CBP showed stronger correlation with PD-L1 expression than p300. No correlation between HDAC2/3 with CD274 (p > 0.05). CD274, EP300, CREBBP, IRF1, and BRD4 ranks negatively correlated to GG, while negative regulators of PD-L1 expression (HDAC1, HDAC2 and HDAC3) seemed insignificant during the cancer progression. CD274, EP300 and CREBBP negatively correlated to overall survival.
Expression levels of CD274 and PDCD1 were associated with increased number of tumor-infiltrating immune cells.
[108]NR (TCGA)NRIn TCGA series, PD-L1 expression was positively associated to lncAMPC (long non-coding RNA NR_046357.1)-activated LIF levels and RNF165 gene transcripts.
[46,83]535 (RP) (°)GG: 1–5
Stage: pT2–3b
Significant correlations between mir-424-3p (in situ hybridization) and the following: high GG (r = 0.12, p = 0.014); GG ≥8 (r = 0.11, p = 0.024); large tumor size (>20 mm, r = 0.13, p = 0.013); perineural infltration (r = 0.11, p = 0.030); vascular invasion (r = 0.12, p = 0.014); CTLA-4 (r = 0.10; p < 0.001); and PD-L1 (cut-off: mean value = 0; r = 0.11; p = 0.040) immunohistochemical expression by tumor cells (°). miR-424-3p did not correlate to any T cell subsets. CTLA-4 did not correlate to any clinicopathological variables, while it was associated with: PD-1 expression on tumor cells (r = 0,10, p = 0.054) and stromal cells (r = 0.16; p = 0.002); CD3+ (p = 0.028) and CD4+
(p = 0.009) T cells. On multivariate analysis, perineural infiltration, pT stage, pT3b, GG, GG ≥4, and positive surgical margins (either apical or non-apical) were significant for poor BRFS. Low miR-424-3p expression (HR: 0.44, 95% CI 0.22–0.87, p = 0.018) was associated with aggressive disease and poor clinical failure-free survival.
[14]262 (RP)
374 (TCGA)
GG: 2-3
Stage: T2-4 N0-1
PD-L1 positivity rate (immunohistochemistry, clone E1L3N, Cell Signaling Technology) was significantly higher in samples showing WDR5 overexpression. The TCGA database confirmed a positive correlation between WDR5 and PD-L1 mRNA levels.
(°): for PD-L1 and CTLA-4 correlations, a previous series of 402 RP was used [83]. BPT: benign prostatic tissue; BRFS: biochemical recurrence-free survival; CI: Confidence Interval; ff: fresh frozen tissue; GG: Grade Group; HR: hazard radio; mCRPC: metastatic castration-resistant prostate cancer; mCXCL12: methylation of CXCL12; mPD-L1: methylation of PD-L1 promoter; MTS: metastases; NR: not reported; PC: prostate cancer; PCR: Polymerase chain reaction; pePD-L1: PD-L1 protein expression; Ref: reference; RP: radical prostatectomy; TC: training cohort; TCGA: The Cancer Genome Atlas database; VC: validation cohort.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Palicelli, A.; Croci, S.; Bisagni, A.; Zanetti, E.; De Biase, D.; Melli, B.; Sanguedolce, F.; Ragazzi, M.; Zanelli, M.; Chaux, A.; et al. What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1. Int. J. Mol. Sci. 2021, 22, 12314. https://doi.org/10.3390/ijms222212314

AMA Style

Palicelli A, Croci S, Bisagni A, Zanetti E, De Biase D, Melli B, Sanguedolce F, Ragazzi M, Zanelli M, Chaux A, et al. What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1. International Journal of Molecular Sciences. 2021; 22(22):12314. https://doi.org/10.3390/ijms222212314

Chicago/Turabian Style

Palicelli, Andrea, Stefania Croci, Alessandra Bisagni, Eleonora Zanetti, Dario De Biase, Beatrice Melli, Francesca Sanguedolce, Moira Ragazzi, Magda Zanelli, Alcides Chaux, and et al. 2021. "What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1" International Journal of Molecular Sciences 22, no. 22: 12314. https://doi.org/10.3390/ijms222212314

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop