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Cancers
Special Issues
Mechanisms of Immunosuppression in Cancer
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Mechanisms of Immunosuppression in Cancer

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

Deadline for manuscript submissions: closed (30 December 2023) | Viewed by 21692

Special Issue Editor

Dr. Shweta Joshi

E-Mail Website
Guest Editor
Department of Pediatrics, Moores Cancer Center, University of California, San Diego, CA, USA
Interests: immuno-oncology; macrophages; myeloid-derived suppressor cells; immunotherapy; immune-suppression in cancer; tumor microenvironment; solid tumors; metastasis

Special Issue Information

Dear Colleagues,

Cancer immunotherapy, including immune checkpoint blockade or adoptive cell therapy, has provided remarkable clinical benefit to some patients, while a significant fraction of patients get minimal or no benefit from this therapy. Tumor cells employ multiple mechanisms to evade immune responses, establishing an immunosuppressive tumor microenvironment that promotes resistance to immunotherapy.

Tumor-induced immunosuppression hampers and modulates the activity of cytotoxic T cells and NK cells through the secretion of various cytokines and metabolites, and recruitment of immunosuppressive cells such as myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells, and regulatory B cells. Hence, it is crucial to understand various tumor-induced immunosuppressive mechanisms to design and develop effective novel immunotherapies and to refine approaches to improve currently available immunotherapies.

This Special Issue invites original research articles and review articles to address the mechanisms of tumor-induced immunosuppression, major impediments for effective antitumor immunity, and approaches to convert ‘cold tumors’ into ‘hot tumors’, which are focused on but not limited to the reprogramming of immune cells, novel immune checkpoints, normalizing tumor vasculature, cytokine modulation, metabolic intervention, targeting exosomes, and strategies to block the infiltration of immunosuppressive cells in the tumor bed.

Dr. Shweta Joshi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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.

Keywords

  • immunosuppression
  • immune cells
  • tumor microenvironment
  • immunotherapy
  • immune checkpoint blockade

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Published Papers (3 papers)

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Research

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21 pages, 719 KiB  
Article
Amino Acid-Metabolizing Enzymes in Advanced High-Grade Serous Ovarian Cancer Patients: Value of Ascites as Biomarker Source and Role for IL4I1 and IDO1
by Yvonne Grobben, Judith E. den Ouden, Cristina Aguado, Anne M. van Altena, Aletta D. Kraneveld and Guido J. R. Zaman
Cancers 2023, 15(3), 893; https://doi.org/10.3390/cancers15030893 - 31 Jan 2023
Cited by 10 | Viewed by 3708
Abstract
The molecular mechanisms contributing to immune suppression in ovarian cancer are not well understood, hampering the successful application of immunotherapy. Amino acid-metabolizing enzymes are known to contribute to the immune-hostile environment of various tumors through depletion of amino acids and production of immunosuppressive [...] Read more.
The molecular mechanisms contributing to immune suppression in ovarian cancer are not well understood, hampering the successful application of immunotherapy. Amino acid-metabolizing enzymes are known to contribute to the immune-hostile environment of various tumors through depletion of amino acids and production of immunosuppressive metabolites. We aimed to collectively evaluate the activity of these enzymes in high-grade serous ovarian cancer patients by performing targeted metabolomics on plasma and ascites samples. Whereas no indication was found for enhanced l-arginine or l-glutamine metabolism by immunosuppressive enzymes in ovarian cancer patients, metabolism of l-tryptophan by indoleamine 2,3-dioxygenase 1 (IDO1) was significantly elevated compared to healthy controls. Moreover, high levels of l-phenylalanine- and l-tyrosine-derived metabolites associated with interleukin 4 induced 1 (IL4I1) activity were found in ovarian cancer ascites samples. While l-tryptophan is a major substrate of both IDO1 and IL4I1, only its enhanced conversion into l-kynurenine by IDO1 could be detected, despite the observed activity of IL4I1 on its other substrates. In ascites of ovarian cancer patients, metabolite levels were higher compared to those in plasma, demonstrating the value of utilizing this fluid for biomarker identification. Finally, elevated metabolism of l-phenylalanine and l-tyrosine by IL4I1 correlated with disease stage, pointing towards a potential role for IL4I1 in ovarian cancer progression. Full article
(This article belongs to the Special Issue Mechanisms of Immunosuppression in Cancer)
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14 pages, 4016 KiB  
Article
BAP1 Loss Promotes Suppressive Tumor Immune Microenvironment via Upregulation of PROS1 in
Class 2 Uveal Melanomas
by Christopher J. Kaler, James J. Dollar, Anthony M. Cruz, Jeffim N. Kuznetsoff, Margaret I. Sanchez, Christina L. Decatur, Jonathan D. Licht, Keiran S. M. Smalley, Zelia M. Correa, Stefan Kurtenbach and J. William Harbour
Cancers 2022, 14(15), 3678; https://doi.org/10.3390/cancers14153678 - 28 Jul 2022
Cited by 21 | Viewed by 6148
Abstract
Uveal melanoma (UM) is the most common primary cancer of the eye and is associated with a high rate of metastatic death. UM can be stratified into two main classes based on metastatic risk, with class 1 UM having a low metastatic risk [...] Read more.
Uveal melanoma (UM) is the most common primary cancer of the eye and is associated with a high rate of metastatic death. UM can be stratified into two main classes based on metastatic risk, with class 1 UM having a low metastatic risk and class 2 UM having a high metastatic risk. Class 2 UM have a distinctive genomic, transcriptomic, histopathologic, and clinical phenotype characterized by biallelic inactivation of the BAP1 tumor-suppressor gene, an immune-suppressive microenvironment enriched for M2-polarized macrophages, and poor response to checkpoint-inhibitor immunotherapy. To identify potential mechanistic links between BAP1 loss and immune suppression in class 2 UM, we performed an integrated analysis of UM samples, as well as genetically engineered UM cell lines and uveal melanocytes (UMC). Using RNA sequencing (RNA-seq), we found that the most highly upregulated gene associated with BAP1 loss across these datasets was PROS1, which encodes a ligand that triggers phosphorylation and activation of the immunosuppressive macrophage receptor MERTK. The inverse association between BAP1 and PROS1 in class 2 UM was confirmed by single-cell RNA-seq, which also revealed that MERTK was upregulated in CD163+ macrophages in class 2 UM. Using ChIP-seq, BAP1 knockdown in UM cells resulted in an accumulation of H3K27ac at the PROS1 locus, suggesting epigenetic regulation of PROS1 by BAP1. Phosphorylation of MERTK in RAW 264.7 monocyte–macrophage cells was increased upon coculture with BAP1−/− UMCs, and this phosphorylation was blocked by depletion of PROS1 in the UMCs. These findings were corroborated by multicolor immunohistochemistry, where class 2/BAP1-mutant UMs demonstrated increased PROS1 expression in tumor cells and increased MERTK phosphorylation in CD163+ macrophages compared with class 1/BAP1-wildtype UMs. Taken together, these findings provide a mechanistic link between BAP1 loss and the suppression of the tumor immune microenvironment in class 2 UMs, and they implicate the PROS1–MERTK pathway as a potential target for immunotherapy in UM. Full article
(This article belongs to the Special Issue Mechanisms of Immunosuppression in Cancer)
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Review

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31 pages, 8029 KiB  
Review
Recent Advances in Molecular Mechanisms of Cancer Immunotherapy
by Mateusz Kciuk, Esam Bashir Yahya, Montaha Mohamed Ibrahim Mohamed, Summya Rashid, Muhammad Omer Iqbal, Renata Kontek, Muhanad A. Abdulsamad and Abdulmutalib A. Allaq
Cancers 2023, 15(10), 2721; https://doi.org/10.3390/cancers15102721 - 11 May 2023
Cited by 45 | Viewed by 10696
Abstract
Cancer is among the current leading causes of death worldwide, despite the novel advances that have been made toward its treatment, it is still considered a major public health concern. Considering both the serious impact of cancer on public health and the significant [...] Read more.
Cancer is among the current leading causes of death worldwide, despite the novel advances that have been made toward its treatment, it is still considered a major public health concern. Considering both the serious impact of cancer on public health and the significant side effects and complications of conventional therapeutic options, the current strategies towards targeted cancer therapy must be enhanced to avoid undesired toxicity. Cancer immunotherapy has become preferable among researchers in recent years compared to conventional therapeutic options, such as chemotherapy, surgery, and radiotherapy. The understanding of how to control immune checkpoints, develop therapeutic cancer vaccines, genetically modify immune cells as well as enhance the activation of antitumor immune response led to the development of novel cancer treatments. In this review, we address recent advances in cancer immunotherapy molecular mechanisms. Different immunotherapeutic approaches are critically discussed, focusing on the challenges, potential risks, and prospects involving their use. Full article
(This article belongs to the Special Issue Mechanisms of Immunosuppression in Cancer)
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