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Insights into anti-tumor immunity via the polyomavirus shared across human Merkel cell carcinomas

Understanding and augmenting cancer-specific immunity is impeded by the fact that most tumors are driven by patient-specific mutations that encode unique antigenic epitopes. The shared antigens in virus-driven tumors can help overcome this limitation. Merkel cell carcinoma (MCC) is a particularly in...

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Autores principales: Jani, Saumya, Church, Candice D., Nghiem, Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10242112/
https://www.ncbi.nlm.nih.gov/pubmed/37287968
http://dx.doi.org/10.3389/fimmu.2023.1172913
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author Jani, Saumya
Church, Candice D.
Nghiem, Paul
author_facet Jani, Saumya
Church, Candice D.
Nghiem, Paul
author_sort Jani, Saumya
collection PubMed
description Understanding and augmenting cancer-specific immunity is impeded by the fact that most tumors are driven by patient-specific mutations that encode unique antigenic epitopes. The shared antigens in virus-driven tumors can help overcome this limitation. Merkel cell carcinoma (MCC) is a particularly interesting tumor immunity model because (1) 80% of cases are driven by Merkel cell polyomavirus (MCPyV) oncoproteins that must be continually expressed for tumor survival; (2) MCPyV oncoproteins are only ~400 amino acids in length and are essentially invariant between tumors; (3) MCPyV-specific T cell responses are robust and strongly linked to patient outcomes; (4) anti-MCPyV antibodies reliably increase with MCC recurrence, forming the basis of a standard clinical surveillance test; and (5) MCC has one of the highest response rates to PD-1 pathway blockade among all solid cancers. Leveraging these well-defined viral oncoproteins, a set of tools that includes over 20 peptide-MHC class I tetramers has been developed to facilitate the study of anti-tumor immunity across MCC patients. Additionally, the highly immunogenic nature of MCPyV oncoproteins forces MCC tumors to develop robust immune evasion mechanisms to survive. Indeed, several immune evasion mechanisms are active in MCC, including transcriptional downregulation of MHC expression by tumor cells and upregulation of inhibitory molecules including PD-L1 and immunosuppressive cytokines. About half of patients with advanced MCC do not persistently benefit from PD-1 pathway blockade. Herein, we (1) summarize the lessons learned from studying the anti-tumor T cell response to virus-positive MCC; (2) review immune evasion mechanisms in MCC; (3) review mechanisms of resistance to immune-based therapies in MCC and other cancers; and (4) discuss how recently developed tools can be used to address open questions in cancer immunotherapy. We believe detailed investigation of this model cancer will provide insight into tumor immunity that will likely also be applicable to more common cancers without shared tumor antigens.
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spelling pubmed-102421122023-06-07 Insights into anti-tumor immunity via the polyomavirus shared across human Merkel cell carcinomas Jani, Saumya Church, Candice D. Nghiem, Paul Front Immunol Immunology Understanding and augmenting cancer-specific immunity is impeded by the fact that most tumors are driven by patient-specific mutations that encode unique antigenic epitopes. The shared antigens in virus-driven tumors can help overcome this limitation. Merkel cell carcinoma (MCC) is a particularly interesting tumor immunity model because (1) 80% of cases are driven by Merkel cell polyomavirus (MCPyV) oncoproteins that must be continually expressed for tumor survival; (2) MCPyV oncoproteins are only ~400 amino acids in length and are essentially invariant between tumors; (3) MCPyV-specific T cell responses are robust and strongly linked to patient outcomes; (4) anti-MCPyV antibodies reliably increase with MCC recurrence, forming the basis of a standard clinical surveillance test; and (5) MCC has one of the highest response rates to PD-1 pathway blockade among all solid cancers. Leveraging these well-defined viral oncoproteins, a set of tools that includes over 20 peptide-MHC class I tetramers has been developed to facilitate the study of anti-tumor immunity across MCC patients. Additionally, the highly immunogenic nature of MCPyV oncoproteins forces MCC tumors to develop robust immune evasion mechanisms to survive. Indeed, several immune evasion mechanisms are active in MCC, including transcriptional downregulation of MHC expression by tumor cells and upregulation of inhibitory molecules including PD-L1 and immunosuppressive cytokines. About half of patients with advanced MCC do not persistently benefit from PD-1 pathway blockade. Herein, we (1) summarize the lessons learned from studying the anti-tumor T cell response to virus-positive MCC; (2) review immune evasion mechanisms in MCC; (3) review mechanisms of resistance to immune-based therapies in MCC and other cancers; and (4) discuss how recently developed tools can be used to address open questions in cancer immunotherapy. We believe detailed investigation of this model cancer will provide insight into tumor immunity that will likely also be applicable to more common cancers without shared tumor antigens. Frontiers Media S.A. 2023-05-23 /pmc/articles/PMC10242112/ /pubmed/37287968 http://dx.doi.org/10.3389/fimmu.2023.1172913 Text en Copyright © 2023 Jani, Church and Nghiem https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Jani, Saumya
Church, Candice D.
Nghiem, Paul
Insights into anti-tumor immunity via the polyomavirus shared across human Merkel cell carcinomas
title Insights into anti-tumor immunity via the polyomavirus shared across human Merkel cell carcinomas
title_full Insights into anti-tumor immunity via the polyomavirus shared across human Merkel cell carcinomas
title_fullStr Insights into anti-tumor immunity via the polyomavirus shared across human Merkel cell carcinomas
title_full_unstemmed Insights into anti-tumor immunity via the polyomavirus shared across human Merkel cell carcinomas
title_short Insights into anti-tumor immunity via the polyomavirus shared across human Merkel cell carcinomas
title_sort insights into anti-tumor immunity via the polyomavirus shared across human merkel cell carcinomas
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10242112/
https://www.ncbi.nlm.nih.gov/pubmed/37287968
http://dx.doi.org/10.3389/fimmu.2023.1172913
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