The Portrait of Cancer Immunotherapy: Tumor Microenvironment, Biomarkers and Immune Resistance—Volume II

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (20 September 2023) | Viewed by 4154

Special Issue Editor

Special Issue Information

Dear Colleagues,

This Special Issue is the second edition of a previous issue on the topic of “The Portrait of Cancer Immunotherapy: Tumor Microenvironment, Biomarkers and Immune Resistance”.

The exploitation of immune lymphocytes’ capacity to specifically recognize and destroy autologous tumor cells has revolutionized the treatment paradigm across a variety of human cancers. Cancer immunotherapy has made several major breakthroughs in the past few years, and immune checkpoint blockade (ICB) has become the cutting-edge therapy for many cancer types with persisting clinical responses. Nevertheless, enthusiasm about the use of ICB in cancer immunotherapy has been significantly mitigated by the fact that only 20%–30% of patients respond to this type of treatment. This underscores the importance to more precisely investigate the complex interactions between tumors and the various elements and factors within the tumor microenvironment (TME) that comprise or modulate the antitumor immune response. This will lead to a better understanding of the immune context of the TME and its role in generating antitumor immunity or immune resistance, thus providing the mechanistic impact for novel combination therapies. On this basis, high-throughput analyses of tumor specimens, peripheral blood, and multiplex imaging followed by computational analyses are imperative for the identification of novel biomarkers or biomarker signatures to optimize immunotherapies.

In this Special Issue, experts in the field of cancer immunotherapy will review the role of the TME in regulating clinical responses during immunotherapies by promoting antitumor immunity or immune resistance, and will discuss recent therapeutic modalities that modulate the TME to reinforce preexisting or therapy-induced antitumor immunity. The predictive role of biomarkers in the peripheral blood for immunotherapy efficacy in patients with various types of cancer will also be reviewed.

Moreover, this Special Issue will include new research articles related to research into a broad range of immunotherapy treatments including cellular therapies, vaccines, and ICB; the identification of new predictive biomarkers and therapeutic targets in the TME and peripheral blood; novel therapeutic approaches; and the use of immune modulators to overcome immune resistance. Results from multicenter clinical studies discovering novel prognostic and/or predictive signatures will also be covered.

Dr. Constantin N. Baxevanis
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (3 papers)

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Research

20 pages, 8346 KiB  
Article
Stress Keratin 17 Is a Predictive Biomarker Inversely Associated with Response to Immune Check-Point Blockade in Head and Neck Squamous Cell Carcinomas and Beyond
Cancers 2023, 15(19), 4905; https://doi.org/10.3390/cancers15194905 - 09 Oct 2023
Cited by 1 | Viewed by 1675
Abstract
Low response rates in immune check-point blockade (ICB)-treated head and neck squamous cell carcinoma (HNSCC) drive a critical need for robust, clinically validated predictive biomarkers. Our group previously showed that stress keratin 17 (CK17) suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated [...] Read more.
Low response rates in immune check-point blockade (ICB)-treated head and neck squamous cell carcinoma (HNSCC) drive a critical need for robust, clinically validated predictive biomarkers. Our group previously showed that stress keratin 17 (CK17) suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors, correlating with decreased response rate to pembrolizumab-based therapy in a pilot cohort of ICB-treated HNSCC (n = 26). Here, we performed an expanded analysis of the predictive value of CK17 in ICB-treated HNSCC according to the REMARK criteria and investigated the gene expression profiles associated with high CK17 expression. Pretreatment samples from pembrolizumab-treated HNSCC patients were stained via immunohistochemistry using a CK17 monoclonal antibody (n = 48) and subjected to spatial transcriptomic profiling (n = 8). Our findings were validated in an independent retrospective cohort (n = 22). CK17 RNA expression in pembrolizumab-treated patients with various cancer types was investigated for predictive significance. Of the 48 patients (60% male, median age of 61.5 years), 21 (44%) were CK17 high, and 27 (56%) were CK17 low. A total of 17 patients (35%, 77% CK17 low) had disease control, while 31 patients (65%, 45% CK17 low) had progressive disease. High CK17 expression was associated with a lack of disease control (p = 0.037), shorter time to treatment failure (p = 0.025), and progression-free survival (PFS, p = 0.004), but not overall survival (OS, p = 0.06). A high CK17 expression was associated with lack of disease control in an independent validation cohort (p = 0.011). PD-L1 expression did not correlate with CK17 expression or clinical outcome. CK17 RNA expression was predictive of PFS and OS in 552 pembrolizumab-treated cancer patients. Our findings indicate that high CK17 expression may predict resistance to ICB in HNSCC patients and beyond. Full article
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16 pages, 2794 KiB  
Article
A Blood-Based Immune Gene Signature with Prognostic Significance in Localized Prostate Cancer
Cancers 2023, 15(14), 3697; https://doi.org/10.3390/cancers15143697 - 20 Jul 2023
Cited by 1 | Viewed by 957
Abstract
Prostate cancer (PCa) is one of the most common male cancers worldwide and one of the deadliest if unsuccessfully treated. Τhe need for reliable, easily accessible immune-related molecular biomarkers that could be combined with clinically defined criteria, including PSA and Gleason score, to [...] Read more.
Prostate cancer (PCa) is one of the most common male cancers worldwide and one of the deadliest if unsuccessfully treated. Τhe need for reliable, easily accessible immune-related molecular biomarkers that could be combined with clinically defined criteria, including PSA and Gleason score, to accurately predict PCa patients’ clinical outcomes is emerging. Herein, we describe for the first time a blood-identified immune-related gene signature comprising eight upregulated multi-functional genes associated with poor prognosis. Next-generation sequencing (NGS) analysis of PCa patients’ peripheral blood samples revealed a more than three-fold upregulation of each of the eight genes as compared to samples originating from healthy donors. The construction of gene and protein interaction networks revealed different extents of the functional implications of these genes in the regulation of cell proliferation and immune responses. Analysis of the available data from The Cancer Genome Atlas (TCGA) regarding gene expression and survival of prostate adenocarcinoma (PRAD) and pan-cancer (PANCAN) patients revealed that intra-tumoral upregulation of this eight-gene signature (8-GS) was associated with poor 5-year progression-free intervals in PCa patients, even in those with high Gleason scores, and also with an unfavorable prognosis for cancer patients irrespective of the cancer type and even in the early stages. These observations suggest that further investigation of the 8-GS prospectively in randomized clinical trials, in which clinical benefit in terms of evaluating time to disease progression can be assessed, is warranted. Full article
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14 pages, 6751 KiB  
Article
The Subtype Identity of Testicular Cancer Cells Determines Their Immunostimulatory Activity in a Coculture Model
Cancers 2023, 15(9), 2619; https://doi.org/10.3390/cancers15092619 - 05 May 2023
Viewed by 1127
Abstract
Testicular germ cell cancer (TGCC) is subdivided into several subtypes. While seminomatous germ cell tumors (SGCT) are characterized by an intensive infiltration of immune cells which constitute a pro-inflammatory tumor micromilieu (TME), immune cells in non-seminomatous germ cell tumors (NSGCT) are differently composed [...] Read more.
Testicular germ cell cancer (TGCC) is subdivided into several subtypes. While seminomatous germ cell tumors (SGCT) are characterized by an intensive infiltration of immune cells which constitute a pro-inflammatory tumor micromilieu (TME), immune cells in non-seminomatous germ cell tumors (NSGCT) are differently composed and less abundant. Previously, we have shown that the seminomatous cell line TCam-2 promotes T cell and monocyte activation in a coculture model, resulting in mutual interactions between both cell types. Here we set out to compare this feature of TCam-2 cells with the non-seminomatous cell line NTERA-2. Peripheral blood T cells or monocytes cocultured with NTERA-2 cells failed to secrete relevant amounts of pro-inflammatory cytokines, and significantly downregulated the expression of genes encoding activation markers and effector molecules. In contrast, immune cells cocultured with TCam-2 cells produced IL-2, IL-6 and TNFα, and strongly upregulated the expression of multiple pro-inflammatory genes. Furthermore, the expression of genes involved in proliferation, stemness and subtype specification remained unaltered in NTERA-2 cells during coculture with T cells or monocytes, indicating the absence of mutual interactions. Collectively, our findings uncover fundamental differences between SGCT and NSGCT in their capability to generate a pro-inflammatory TME, which possibly impacts the clinical features and prognosis of both TGCC subtypes. Full article
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