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13 pages, 2071 KiB

Open AccessArticle

Robust Preanalytical Performance of Soluble PD-1, PD-L1 and PD-L2 Assessed by Sensitive ELISAs in Blood

by Kimberly Krueger, Zsuzsanna Mayer, Marc Kottmaier, Miriam Gerckens, Stefan Boeck, Peter Luppa and Stefan Holdenrieder

Biomedicines 2022, 10(10), 2534; https://doi.org/10.3390/biomedicines10102534 - 11 Oct 2022

Cited by 1 | Viewed by 1277

Abstract

The interaction between programmed death-1 receptor PD-1 and its ligands PD-L1 and PD-L2 is involved in self-tolerance, immune escape of cancer, cardiovascular diseases, and COVID-19. As blood-based protein markers they bear great potential to improve oncoimmunology research and monitoring of anti-cancer immunotherapy. A [...] Read more.

The interaction between programmed death-1 receptor PD-1 and its ligands PD-L1 and PD-L2 is involved in self-tolerance, immune escape of cancer, cardiovascular diseases, and COVID-19. As blood-based protein markers they bear great potential to improve oncoimmunology research and monitoring of anti-cancer immunotherapy. A variety of preanalytical conditions were tested to assure high quality plasma sample measurements: (i) different time intervals and storage temperatures before and after blood centrifugation; (ii) fresh samples and repeated freeze–thaw-cycles; (iii) different conditions of sample preparation before measurement. Concerning short-term stability, acceptable recoveries for PD-1 between 80 and 120% were obtained when samples were kept up to 24 h at 4 and 25 °C before and after blood centrifugation. Similarly, recoveries for PD-L2 were acceptable for 24 h at 4 °C and 6 h at 25 °C before blood centrifugation and up to 24 h at 4 and 25 °C after centrifugation. Variations for PD-L1 were somewhat higher, however, at very low signal levels. Sample concentrations (ng/mL) were neither affected by the freezing process nor by repeated freeze–thaw cycles with coefficients of variation for PD-1: 9.1%, PD-L1 6.8%, and PD-L2 4.8%. All three biomarkers showed good stability regarding preanalytic conditions of sample handling enabling reliable and reproducible quantification in oncoimmunology research and clinical settings of anti-cancer immunotherapy. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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18 pages, 4071 KiB

Open AccessArticle

Association of Circular RNA and Long Non-Coding RNA Dysregulation with the Clinical Response to Immune Checkpoint Blockade in Cutaneous Metastatic Melanoma

by Javier Oliver, Juan Luis Onieva, Maria Garrido-Barros, Miguel-Ángel Berciano-Guerrero, Alfonso Sánchez-Muñoz, María José Lozano, Angela Farngren, Martina Álvarez, Beatriz Martínez-Gálvez, Elisabeth Pérez-Ruiz, Emilio Alba, Manuel Cobo, Antonio Rueda-Domínguez and Isabel Barragán

Biomedicines 2022, 10(10), 2419; https://doi.org/10.3390/biomedicines10102419 - 27 Sep 2022

Cited by 2 | Viewed by 2207

Abstract

Cutaneous melanoma (CM) is the most lethal form of skin cancer if it becomes metastatic, where treatment options and survival chances decrease dramatically. Immunotherapy treatments based on the immunologic checkpoint inhibitors programmed death cell protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) [...] Read more.

Cutaneous melanoma (CM) is the most lethal form of skin cancer if it becomes metastatic, where treatment options and survival chances decrease dramatically. Immunotherapy treatments based on the immunologic checkpoint inhibitors programmed death cell protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) constituted a main breakthrough in the treatment of metastatic CM, particularly for the achievement of long-term benefits. Even though it is a very promising therapy, resistance to primary immune checkpoint blockade (ICB) arises in about 70% of CM patients treated with a CTLA-4 inhibitor, and 40–65% of CM patients administered with a PD-1-targeting treatment. Some long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are implicated in triggering pro- and anti-tumorigenic responses to various cancer treatments. The relationship between lncRNAs, circRNAs and ICB immunotherapy has not been explored in cutaneous metastatic melanoma (CMM). The aim of this pilot study is to evaluate the potential role of circRNA and lncRNA expression variability as pre-treatment predictor of the clinical response to immunotherapy in CMM patients. RNA-seq from 12 formalin-fixed paraffin-embedded (FFPE) samples from the metastatic biopsies of CMM patients treated with nivolumab was used to identify response-associated transcripts. Our findings indicate that specific lncRNAs and circRNAs, probably acting as competitive endogenous RNAs (ceRNAs), are involved in the regulatory networks of the immune response against metastatic melanoma that these patients have under treatment with nivolumab. Moreover, we established a risk score that yields predictions of the overall survival (OS) and progression-free survival (PFS) of CMM patients with high accuracy. This proof-of-principle work provides a possible insight into the function of ceRNAs, contributing to efforts to decipher the complex molecular mechanisms of ICB cancer treatment response. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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13 pages, 1243 KiB

Open AccessArticle

High Quality Performance of Novel Immunoassays for the Sensitive Quantification of Soluble PD-1, PD-L1 and PD-L2 in Blood

by Kimberly Krueger, Zsuzsanna Mayer, Miriam Gerckens, Stefan Boeck, Peter Luppa and Stefan Holdenrieder

Biomedicines 2022, 10(10), 2405; https://doi.org/10.3390/biomedicines10102405 - 26 Sep 2022

Cited by 6 | Viewed by 1413

Abstract

Programmed death-1 receptor PD-1(CD279) and its corresponding ligands PD-L1(CD274, B7-H1) and PD-L2(CD273, B7-DC) play important roles in physiological immune tolerance and for immune escape in cancer disease. Hence, the establishment and analytical validation of a novel enzyme-linked immunosorbent assay (ELISA) to measure soluble [...] Read more.

Programmed death-1 receptor PD-1(CD279) and its corresponding ligands PD-L1(CD274, B7-H1) and PD-L2(CD273, B7-DC) play important roles in physiological immune tolerance and for immune escape in cancer disease. Hence, the establishment and analytical validation of a novel enzyme-linked immunosorbent assay (ELISA) to measure soluble PD-1, PD-L1 and PD-L2 in blood samples according to high quality standards is required. Antibody pairs were used to establish novel highly sensitive ELISAs for all three markers on an open electrochemiluminescence Quickplex platform. Analytical validation comprised intra- and interassay imprecision, limit of quantification, dilution linearity, material comparison and analytical selectivity testing. The methods demonstrated a broad dynamic range and precise measurements down to the pg/mL range. The coefficient of variation (CV) during the intra-assay imprecision measurements with three patient pools did not exceed 10% for all three assays (PD-1: 6.4%, 6.5%, 7.8%, PD-L1: 7.1%, 4.2%, 6.8%; PD-L2: 4.5%, 10.0%, 9.9%). Dilution linearity experiments in both buffer and heparin plasma displayed good linearity. Selectivity was shown for each marker in titration cross-reactivity experiments up to concentrations of at least 15 ng/mL of these, possibly confounding other markers. Soluble PD-1, PD-L1 and PD-L2 can be measured highly sensitively in serum and plasma and can safely be applied to clinical study settings. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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10 pages, 541 KiB

Open AccessArticle

Safety of FOLFIRI + Durvalumab +/− Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59

by Camille Evrard, Thomas Aparicio, Emilie Soularue, Karine Le Malicot, Jérôme Desramé, Damien Botsen, Farid El Hajbi, Daniel Gonzalez, Come Lepage, Olivier Bouché, David Tougeron and on behalf of the DURIGAST—PRODIGE 59 Investigators/Collaborators

Biomedicines 2022, 10(5), 1211; https://doi.org/10.3390/biomedicines10051211 - 23 May 2022

Cited by 4 | Viewed by 2051

Abstract

Efficacy of immune checkpoint inhibitors (ICI) as monotherapy in 2nd line treatment for gastric or gastro-oesophageal junction (GEJ) adenocarcinoma is low, with no evaluation of efficacy and safety of ICI combined with chemotherapy. The DURIGAST PRODIGE 59 study is a randomised, multicentre, phase [...] Read more.

Efficacy of immune checkpoint inhibitors (ICI) as monotherapy in 2nd line treatment for gastric or gastro-oesophageal junction (GEJ) adenocarcinoma is low, with no evaluation of efficacy and safety of ICI combined with chemotherapy. The DURIGAST PRODIGE 59 study is a randomised, multicentre, phase II study designed to assess the efficacy and safety of the combination of FOLFIRI + Durvalumab +/− Tremelimumab as 2nd line treatment of patients with advanced gastric/GEJ adenocarcinoma. Here, we report data from the safety run-in phase with FOLFIRI Durvalumab (arm A) or FOLFIRI Durvalumab and Tremelimumab (arm B). Among the 11 patients included, 63.6% experienced at least one grade 3–4 adverse events (AEs) related to the treatment, most frequently neutropenia (36.4%). There was only one immune-related AE (grade 2 hyperthyroidism). Ten serious AEs were described among six patients, but only two were related to the treatment, due to the chemotherapy. One seizure epilepsy related to a brain metastasis was observed, but was not related by the investigator to the treatment. However, the Independent Data Monitoring Committee recommended brain imaging at inclusion. This safety run-in phase demonstrates an expected safety profile of FOLFIRI with Durvalumab +/− Tremelimumab combination allowing the randomised phase II. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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14 pages, 1823 KiB

Open AccessArticle

HDAC Inhibition for Optimized Cellular Immunotherapy of NY-ESO-1-Positive Soft Tissue Sarcoma

by Wenjie Gong, Lei Wang, Maria-Luisa Schubert, Christian Kleist, Brigitte Neuber, Sanmei Wang, Mingya Yang, Angela Hückelhoven-Krauss, Depei Wu, Anita Schmitt, Carsten Müller-Tidow, Hiroshi Shiku, Michael Schmitt and Leopold Sellner

Biomedicines 2022, 10(2), 373; https://doi.org/10.3390/biomedicines10020373 - 03 Feb 2022

Cited by 2 | Viewed by 1623

Abstract

Adoptive cell therapy with NY-ESO-1-specific T cells is a promising option for the treatment of soft tissue sarcoma (STS) but achieves only transient tumor control in the majority of cases. A strategy to optimize this cell therapeutic approach might be the modulation of [...] Read more.

Adoptive cell therapy with NY-ESO-1-specific T cells is a promising option for the treatment of soft tissue sarcoma (STS) but achieves only transient tumor control in the majority of cases. A strategy to optimize this cell therapeutic approach might be the modulation of the expression of the cancer-testis antigen NY-ESO-1 using histone deacetylase inhibitors (HDACis). In this study, the ex vivo effect of combining NY-ESO-1-specific T cells with the clinically approved pan HDACis panobinostat or vorionstat was investigated. Our data demonstrated that STS cells were sensitive to HDACis. Administration of HDACi prior to NY-ESO-1-specific T cells exerted enhanced lysis against the NY-ESO-1+ STS cell line SW982. This correlated with an increase in the NY-ESO-1 and HLA-ABC expression of SW982 cells, as well as increased CD25 expression on NY-ESO-1-specific T cells. Furthermore, the immune reactivity of NY-ESO-1-specific CD8+ T cells in terms of cytokine release was enhanced by HDACis. In summary, pretreatment with HDACis represents a potential means of enhancing the cytotoxic efficacy of NY-ESO-1-specific T cells against NY-ESO-1-positive STS. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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17 pages, 5744 KiB

Open AccessArticle

PBK/TOPK Is a Favorable Prognostic Biomarker Correlated with Antitumor Immunity in Colon Cancers

by Dong-Hee Lee, Yu-Jeong Jeong, Ju-Young Won, Hye-In Sim, Yoon Park and Hyung-Seung Jin

Biomedicines 2022, 10(2), 299; https://doi.org/10.3390/biomedicines10020299 - 27 Jan 2022

Cited by 3 | Viewed by 2777

Abstract

Immune checkpoint inhibitor therapy has proven efficacy in a subset of colon cancer patients featuring a deficient DNA mismatch repair system or a high microsatellite instability profile. However, there is high demand for more effective biomarkers to expand the colon cancer population responding [...] Read more.

Immune checkpoint inhibitor therapy has proven efficacy in a subset of colon cancer patients featuring a deficient DNA mismatch repair system or a high microsatellite instability profile. However, there is high demand for more effective biomarkers to expand the colon cancer population responding to ICI therapy. PBK/TOPK, a serine/threonine kinase, plays a role in cell cycle regulation and mitotic progression. Here, we investigated the correlation between PBK/TOPK expression and tumor immunity and its prognostic value in colon cancer. Based on large-scale bioinformatics analysis, we discovered that elevated PBK/TOPK expression predicted a favorable outcome in patients with colon cancer and was positively associated with immune infiltration levels of CD8+ T cells, CD4+ T cells, natural killer cells, and M1 macrophages. In contrast, a negative correlation was found between PBK/TOPK expression and immune suppressor cells, including regulatory T cells and M2 macrophages. Furthermore, the expression of PBK/TOPK was correlated with the expression of T-cell cytotoxicity genes in colon cancer. Additionally, high PBK/TOPK expression was associated with mutations in DNA damage repair genes, and thus with increased tumor mutation and neoantigen burden. These findings suggest that PBK/TOPK may serve as a prognostic and predictive biomarker for immunotherapy in colon cancer. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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13 pages, 2794 KiB

Open AccessArticle

Relationship between Macrophage and Radiosensitivity in Human Primary and Recurrent Glioblastoma: In Silico Analysis with Publicly Available Datasets

by Bum-Sup Jang and In Ah Kim

Biomedicines 2022, 10(2), 292; https://doi.org/10.3390/biomedicines10020292 - 27 Jan 2022

Cited by 7 | Viewed by 3028

Abstract

The glioblastoma microenvironment predominantly contains tumor-associated macrophages that support tumor growth and invasion. We investigated the relationship between tumor radiosensitivity and infiltrating M1/M2 macrophage profiles in public datasets of primary and recurrent glioblastoma. We estimated the radiosensitivity index (RSI) score based on gene [...] Read more.

The glioblastoma microenvironment predominantly contains tumor-associated macrophages that support tumor growth and invasion. We investigated the relationship between tumor radiosensitivity and infiltrating M1/M2 macrophage profiles in public datasets of primary and recurrent glioblastoma. We estimated the radiosensitivity index (RSI) score based on gene expression rankings. Macrophages were profiled using the deconvolution algorithm CIBERSORTx. Samples from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), the Ivy Glioblastoma Atlas Project dataset, a single-cell RNA sequencing dataset (GSE84465), Glioma Longitudinal Analysis Consortium (GLASS), and an immunotherapy trial dataset (GSE121810) were included. RSI-high radioresistant tumors were associated with worse overall survival in TCGA and CGGA than RSI-low tumors. M1/M2 macrophage ratios and RSI scores were inversely associated, indicating that radioresistant glioblastoma tumor microenvironments contain more M2 than M1 macrophages. In the single-cell RNA sequencing dataset, the mean RSI of neoplastic cells was positively correlated with high M2 macrophages proportions. A favorable response to programmed cell death protein 1 (PD-1) therapy was observed in recurrent glioblastomas with high M1/M2 macrophage ratios and low RSI scores. In patients with recurrent glioblastoma, fewer M2 macrophages and low RSI scores were associated with improved overall survival. High M2 macrophage proportions may be involved in radioresistant glioblastoma. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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12 pages, 3750 KiB

Open AccessArticle

A Novel Multi-Mode Thermal Therapy for Colorectal Cancer Liver Metastasis: A Pilot Study

by Wentao Li, Yue Lou, Guangzhi Wang, Kangwei Zhang, Lichao Xu, Ping Liu and Lisa X. Xu

Biomedicines 2022, 10(2), 280; https://doi.org/10.3390/biomedicines10020280 - 26 Jan 2022

Cited by 6 | Viewed by 2281

Abstract

A novel multi-mode thermal therapy was developed for local tumor ablation and the systemic stimulation of anti-tumor immunity, consisting of a rapid liquid nitrogen freezing, and followed by the radiofrequency heating of target tumor tissue. This pilot study aimed to compare the therapeutic [...] Read more.

A novel multi-mode thermal therapy was developed for local tumor ablation and the systemic stimulation of anti-tumor immunity, consisting of a rapid liquid nitrogen freezing, and followed by the radiofrequency heating of target tumor tissue. This pilot study aimed to compare the therapeutic effects of the new therapy with conventional radiofrequency ablation (RFA) on patients with colorectal cancer liver metastasis (CRCLM). From August 2016 to September 2019, thirty-one patients with CRCLM received either multi-mode thermal therapy (n = 17) or RFA (n = 14). Triphasic contrast-enhanced magnetic resonance imaging (MRI), routine blood tests, and peripheral blood immune responses were evaluated before the treatment and in 1, 3, 6, and 12 months after. Local tumor response and progression-free survival (PFS) were assessed using the Kaplan-Meier method, and pre- and post-treatment immune cell counts were analyzed using Mann-Whitney U and Wilcoxon tests. A significantly longer PFS was observed in the multi-mode thermal therapy group in comparison to that of the conventional RFA group (median, 11.4 versus 3.4 months, p = 0.022). It was found that multi-mode therapy induced the functional maturation of dendritic cells, promoted CD4⁺ T cell-mediated antitumor responses, and decreased regulatory T cells, contributing to better therapeutic efficacy in CRCLM patients. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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13 pages, 2103 KiB

Open AccessArticle

Autoantibody to GNAS in Early Detection of Hepatocellular Carcinoma: A Large-Scale Sample Study Combined with Verification in Serial Sera from HCC Patients

by Xiao Wang, Keyan Wang, Cuipeng Qiu, Bofei Wang, Xiaojun Zhang, Yangcheng Ma, Liping Dai and Jian-Ying Zhang

Biomedicines 2022, 10(1), 97; https://doi.org/10.3390/biomedicines10010097 - 04 Jan 2022

Cited by 4 | Viewed by 1613

Abstract

The aim of this study was to explore the value of autoantibody to GNAS in the early detection of hepatocellular carcinoma (HCC). In a large-scale sample set of 912 participants (228 cases in each of HCC, liver cirrhosis (LC), chronic hepatitis B (CHB), [...] Read more.

The aim of this study was to explore the value of autoantibody to GNAS in the early detection of hepatocellular carcinoma (HCC). In a large-scale sample set of 912 participants (228 cases in each of HCC, liver cirrhosis (LC), chronic hepatitis B (CHB), and normal controls (NCs) groups), autoantibody to GNAS was detected with a positive result in 47.8% of HCC patients, which was significantly higher than that in patients with LC (35.1%), CHB (19.7%), and NCs (19.7%). Further analysis showed that the frequency of autoantibody to GNAS started increasing in compensated cirrhosis patients (37.0%) with a jump in decompensated cirrhosis patients (53.2%) and reached a peak in early HCC patients (62.4%). The increasing autoantibody response to GNAS in patients at different stages was closely associated with the progression of chronic liver lesions. The result from 44 human serial sera demonstrated that 5 of 11 (45.5%) HCC patients had elevated autoantibody to GNAS before and/or at diagnosis of HCC. Moreover, 46.1% and 62.4% of high positive rates in alpha-fetoprotein (AFP) negative and early-stage HCC patients can supplement AFP in early detection of HCC. These findings suggest that autoantibody to GNAS could be used as a potential biomarker for the early detection of HCC. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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10 pages, 1394 KiB

Open AccessArticle

Combination Biomarker of Immune Checkpoints Predict Prognosis of Urothelial Carcinoma

by Chung-Ying Tsai, Hsiang-Cheng Chi, Ren-Chin Wu, Cheng-Hao Weng, Tzong-Shyuan Tai, Chan-Yu Lin, Tai-Di Chen, Ya-Hui Wang, Li-Fang Chou, Shen-Hsing Hsu, Po-Hung Lin, See-Tong Pang and Huang-Yu Yang

Biomedicines 2022, 10(1), 8; https://doi.org/10.3390/biomedicines10010008 - 22 Dec 2021

Cited by 3 | Viewed by 2323

Abstract

In contrast to Western counties, the incidence of urothelial carcinoma (UC) remains mar-edly elevated in Taiwan. Regulatory T cells (Tregs) play a crucial role in limiting immune responses within the tumor microenvironment. To elucidate the relationship between immune checkpoints in the tumor immune [...] Read more.

In contrast to Western counties, the incidence of urothelial carcinoma (UC) remains mar-edly elevated in Taiwan. Regulatory T cells (Tregs) play a crucial role in limiting immune responses within the tumor microenvironment. To elucidate the relationship between immune checkpoints in the tumor immune microenvironment and UC progression, we utilize the Gene Expression Omnibus (GEO) to analyze a microarray obtained from 308 patients with UC. We observed that the expression level of CD276 or TIM-3 was positively correlated with late-stage UC and poor prognosis. Patients with simultaneously high CD276 and TIM-3 expression in tumors have significantly reduced both univariate and multivariate survival, indicating that mRNA levels of these immune checkpoints could be independent prognostic biomarkers for UC overall survival and recurrence. Our cohort study showed rare CD8+ cytotoxic T-cells and Tregs infiltration during early-stage UC-known as cold tumors. Approximately 30% of late-stage tumors exhibited highly infiltrated cytotoxic T cells with high PD-1 and FOXP3 expression, which implied that cytotoxic T cells were inhibited in the advanced UC microenvironment. Collectively, our findings provide a better prognosis prediction by combined immune checkpoint biomarkers and a basis for early-stage UC standard treatment to convert cold tumors into hot tumors, followed by immune checkpoint therapy. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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12 pages, 7078 KiB

Open AccessArticle

Embedded Upconversion Nanoparticles in Magnetic Molecularly Imprinted Polymers for Photodynamic Therapy of Hepatocellular Carcinoma

by Cheng-Chih Lin, Hung-Yin Lin, James L. Thomas, Jia-Xin Yu, Chien-Yu Lin, Yu-Hua Chang, Mei-Hwa Lee and Tzong-Liu Wang

Biomedicines 2021, 9(12), 1923; https://doi.org/10.3390/biomedicines9121923 - 15 Dec 2021

Cited by 8 | Viewed by 2462

Abstract

In this work, high-temperature pyrolysis was used to prepare both the core and shell of lantha-nide-doped UCNPs with lithium yttrium tetrafluoride (LiYF₄) to enhance the green luminescence. Merocyanine 540 (MC540)-grafted magnetic nanoparticles were incorporated in the PD-L1 pep-tide-imprinted poly(ethylene-co-vinyl [...] Read more.

In this work, high-temperature pyrolysis was used to prepare both the core and shell of lantha-nide-doped UCNPs with lithium yttrium tetrafluoride (LiYF₄) to enhance the green luminescence. Merocyanine 540 (MC540)-grafted magnetic nanoparticles were incorporated in the PD-L1 pep-tide-imprinted poly(ethylene-co-vinyl alcohol) particles, which were formed by precipitation in a non-solvent. UCNPs in the non-solvent bath were thus entrapped in the imprinted particles to generate composite nanoparticles for the targeting and photodynamic therapy of PD-L1 in tumor cells. Finally, the in vitro cytotoxicity of the nanoparticles in HepG2 human liver cancer cells was evaluated with the continuous administration of MC540/MNPs@MIPs/UCNPs under irradiation by an NIR laser. To understand the delivery of the UCNP-embedded molecularly imprinted pol-ymers, the intrinsic and extrinsic pathways were also investigated. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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Review

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22 pages, 1727 KiB

Open AccessReview

Tumor Temperature: Friend or Foe of Virus-Based Cancer Immunotherapy

by Jason P. Knapp, Julia E. Kakish, Byram W. Bridle and David J. Speicher

Biomedicines 2022, 10(8), 2024; https://doi.org/10.3390/biomedicines10082024 - 19 Aug 2022

Cited by 15 | Viewed by 2691

Abstract

The temperature of a solid tumor is often dissimilar to baseline body temperature and, compared to healthy tissues, may be elevated, reduced, or a mix of both. The temperature of a tumor is dependent on metabolic activity and vascularization and can change due [...] Read more.

The temperature of a solid tumor is often dissimilar to baseline body temperature and, compared to healthy tissues, may be elevated, reduced, or a mix of both. The temperature of a tumor is dependent on metabolic activity and vascularization and can change due to tumor progression, treatment, or cancer type. Despite the need to function optimally within temperature-variable tumors, oncolytic viruses (OVs) are primarily tested at 37 °C in vitro. Furthermore, animal species utilized to test oncolytic viruses, such as mice, dogs, cats, and non-human primates, poorly recapitulate the temperature profile of humans. In this review, we discuss the importance of temperature as a variable for OV immunotherapy of solid tumors. Accumulating evidence supports that the temperature sensitivity of OVs lies on a spectrum, with some OVs likely hindered but others enhanced by elevated temperatures. We suggest that in vitro temperature sensitivity screening be performed for all OVs destined for the clinic to identify potential hinderances or benefits with regard to elevated temperature. Furthermore, we provide recommendations for the clinical use of temperature and OVs. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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16 pages, 744 KiB

Open AccessReview

Therapeutic Strategies to Enhance Tumor Antigenicity: Making the Tumor Detectable by the Immune System

by Daniel Meraviglia-Crivelli, Angelina Zheleva, Martin Barainka, Beatriz Moreno, Helena Villanueva and Fernando Pastor

Biomedicines 2022, 10(8), 1842; https://doi.org/10.3390/biomedicines10081842 - 30 Jul 2022

Cited by 5 | Viewed by 2230

Abstract

Cancer immunotherapy has revolutionized the oncology field, but many patients still do not respond to current immunotherapy approaches. One of the main challenges in broadening the range of responses to this type of treatment is the limited source of tumor neoantigens. T cells [...] Read more.

Cancer immunotherapy has revolutionized the oncology field, but many patients still do not respond to current immunotherapy approaches. One of the main challenges in broadening the range of responses to this type of treatment is the limited source of tumor neoantigens. T cells constitute a main line of defense against cancer, and the decisive step to trigger their activation is mediated by antigen recognition. Antigens allow the immune system to differentiate between self and foreign, which constitutes a critical step in recognition of cancer cells and the consequent development or control of the malignancy. One of the keystones to achieving a successful antitumor response is the presence of potent tumor antigens, known as neoantigens. However, tumors develop strategies to evade the immune system and resist current immunotherapies, and many tumors present a low tumor mutation burden limiting the presence of tumor antigenicity. Therefore, new approaches must be taken into consideration to overcome these shortcomings. The possibility of making tumors more antigenic represents a promising front to further improve the success of immunotherapy in cancer. Throughout this review, we explored different state-of-the-art tools to induce the presentation of new tumor antigens by intervening at protein, mRNA or genomic levels in malignant cells. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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23 pages, 1137 KiB

Open AccessReview

Radionuclide Imaging of Cytotoxic Immune Cell Responses to Anti-Cancer Immunotherapy

by Louis Lauwerys, Evelien Smits, Tim Van den Wyngaert and Filipe Elvas

Biomedicines 2022, 10(5), 1074; https://doi.org/10.3390/biomedicines10051074 - 05 May 2022

Cited by 3 | Viewed by 2689

Abstract

Cancer immunotherapy is an evolving and promising cancer treatment that takes advantage of the body’s immune system to yield effective tumor elimination. Importantly, immunotherapy has changed the treatment landscape for many cancers, resulting in remarkable tumor responses and improvements in patient survival. However, [...] Read more.

Cancer immunotherapy is an evolving and promising cancer treatment that takes advantage of the body’s immune system to yield effective tumor elimination. Importantly, immunotherapy has changed the treatment landscape for many cancers, resulting in remarkable tumor responses and improvements in patient survival. However, despite impressive tumor effects and extended patient survival, only a small proportion of patients respond, and others can develop immune-related adverse events associated with these therapies, which are associated with considerable costs. Therefore, strategies to increase the proportion of patients gaining a benefit from these treatments and/or increasing the durability of immune-mediated tumor response are still urgently needed. Currently, measurement of blood or tissue biomarkers has demonstrated sampling limitations, due to intrinsic tumor heterogeneity and the latter being invasive. In addition, the unique response patterns of these therapies are not adequately captured by conventional imaging modalities. Consequently, non-invasive, sensitive, and quantitative molecular imaging techniques, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) using specific radiotracers, have been increasingly used for longitudinal whole-body monitoring of immune responses. Immunotherapies rely on the effector function of CD8⁺ T cells and natural killer cells (NK) at tumor lesions; therefore, the monitoring of these cytotoxic immune cells is of value for therapy response assessment. Different immune cell targets have been investigated as surrogate markers of response to immunotherapy, which motivated the development of multiple imaging agents. In this review, the targets and radiotracers being investigated for monitoring the functional status of immune effector cells are summarized, and their use for imaging of immune-related responses are reviewed along their limitations and pitfalls, of which multiple have already been translated to the clinic. Finally, emerging effector immune cell imaging strategies and future directions are provided. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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17 pages, 777 KiB

Open AccessReview

Recent Advances of Immune Checkpoint Inhibition and Potential for (Combined) TIGIT Blockade as a New Strategy for Malignant Pleural Mesothelioma

by Sophie Rovers, Annelies Janssens, Jo Raskin, Patrick Pauwels, Jan P. van Meerbeeck, Evelien Smits and Elly Marcq

Biomedicines 2022, 10(3), 673; https://doi.org/10.3390/biomedicines10030673 - 14 Mar 2022

Cited by 4 | Viewed by 2535

Abstract

Malignant pleural mesothelioma (MPM) is a fatal cancer type that affects the membranes lining the lungs, and is causally associated with asbestos exposure. Until recently, the first-line treatment consisted of a combination of chemotherapeutics that only had a limited impact on survival, and [...] Read more.

Malignant pleural mesothelioma (MPM) is a fatal cancer type that affects the membranes lining the lungs, and is causally associated with asbestos exposure. Until recently, the first-line treatment consisted of a combination of chemotherapeutics that only had a limited impact on survival, and had not been improved in decades. With the recent approval of combined immune checkpoint inhibition for MPM, promising new immunotherapeutic strategies are now emerging for this disease. In this review, we describe the current preclinical and clinical evidence of various immune checkpoint inhibitors in MPM. We will consider the advantages of combined immune checkpoint blockade in comparison with single agent checkpoint inhibitor drugs. Furthermore, recent evidence suggests a role for T cell immunoglobulin and ITIM domain (TIGIT), an inhibitory immunoreceptor, as a novel target for immunotherapy. As this novel immune checkpoint remains largely unexplored in mesothelioma, we will discuss the potential of TIGIT blockade as an alternative therapeutic approach for MPM. This review will emphasize the necessity for new and improved treatments for MPM, while highlighting the recent advances and future perspectives of combined immune checkpoint blockade, particularly aimed at PD-L1 and TIGIT. Full article

(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)

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