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Immune escape and resistance to immunotherapy in mismatch repair deficient tumors
Up to 30% of colorectal, endometrial and gastric cancers have a deficiency in mismatch repair (MMR) protein expression due to either germline or epigenetic inactivation. Patients with Lynch Syndrome who inherit an inactive MMR allele have an up to 80% risk for developing a mismatch repair deficient...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10363668/ https://www.ncbi.nlm.nih.gov/pubmed/37492581 http://dx.doi.org/10.3389/fimmu.2023.1210164 |
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author | Mestrallet, Guillaume Brown, Matthew Bozkus, Cansu Cimen Bhardwaj, Nina |
author_facet | Mestrallet, Guillaume Brown, Matthew Bozkus, Cansu Cimen Bhardwaj, Nina |
author_sort | Mestrallet, Guillaume |
collection | PubMed |
description | Up to 30% of colorectal, endometrial and gastric cancers have a deficiency in mismatch repair (MMR) protein expression due to either germline or epigenetic inactivation. Patients with Lynch Syndrome who inherit an inactive MMR allele have an up to 80% risk for developing a mismatch repair deficient (MMRd) cancer. Due to an inability to repair DNA, MMRd tumors present with genomic instability in microsatellite regions (MS). Tumors with high MS instability (MSI-H) are characterized by an increased frequency of insertion/deletions (indels) that can encode novel neoantigens if they occur in coding regions. The high tumor antigen burden for MMRd cancers is accompanied by an inflamed tumor microenvironment (TME) that contributes to the clinical effectiveness of anti-PD-1 therapy in this patient population. However, between 40 and 70% of MMRd cancer patients do not respond to treatment with PD-1 blockade, suggesting that tumor-intrinsic and -extrinsic resistance mechanisms may affect the success of checkpoint blockade. Immune evasion mechanisms that occur during early tumorigenesis and persist through cancer development may provide a window into resistance pathways that limit the effectiveness of anti-PD-1 therapy. Here, we review the mechanisms of immune escape in MMRd tumors during development and checkpoint blockade treatment, including T cell dysregulation and myeloid cell-mediated immunosuppression in the TME. Finally, we discuss the development of new therapeutic approaches to tackle resistance in MMRd tumors, including cancer vaccines, therapies targeting immunosuppressive myeloid programs, and immune checkpoint combination strategies. |
format | Online Article Text |
id | pubmed-10363668 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-103636682023-07-25 Immune escape and resistance to immunotherapy in mismatch repair deficient tumors Mestrallet, Guillaume Brown, Matthew Bozkus, Cansu Cimen Bhardwaj, Nina Front Immunol Immunology Up to 30% of colorectal, endometrial and gastric cancers have a deficiency in mismatch repair (MMR) protein expression due to either germline or epigenetic inactivation. Patients with Lynch Syndrome who inherit an inactive MMR allele have an up to 80% risk for developing a mismatch repair deficient (MMRd) cancer. Due to an inability to repair DNA, MMRd tumors present with genomic instability in microsatellite regions (MS). Tumors with high MS instability (MSI-H) are characterized by an increased frequency of insertion/deletions (indels) that can encode novel neoantigens if they occur in coding regions. The high tumor antigen burden for MMRd cancers is accompanied by an inflamed tumor microenvironment (TME) that contributes to the clinical effectiveness of anti-PD-1 therapy in this patient population. However, between 40 and 70% of MMRd cancer patients do not respond to treatment with PD-1 blockade, suggesting that tumor-intrinsic and -extrinsic resistance mechanisms may affect the success of checkpoint blockade. Immune evasion mechanisms that occur during early tumorigenesis and persist through cancer development may provide a window into resistance pathways that limit the effectiveness of anti-PD-1 therapy. Here, we review the mechanisms of immune escape in MMRd tumors during development and checkpoint blockade treatment, including T cell dysregulation and myeloid cell-mediated immunosuppression in the TME. Finally, we discuss the development of new therapeutic approaches to tackle resistance in MMRd tumors, including cancer vaccines, therapies targeting immunosuppressive myeloid programs, and immune checkpoint combination strategies. Frontiers Media S.A. 2023-07-10 /pmc/articles/PMC10363668/ /pubmed/37492581 http://dx.doi.org/10.3389/fimmu.2023.1210164 Text en Copyright © 2023 Mestrallet, Brown, Bozkus and Bhardwaj 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 Mestrallet, Guillaume Brown, Matthew Bozkus, Cansu Cimen Bhardwaj, Nina Immune escape and resistance to immunotherapy in mismatch repair deficient tumors |
title | Immune escape and resistance to immunotherapy in mismatch repair deficient tumors |
title_full | Immune escape and resistance to immunotherapy in mismatch repair deficient tumors |
title_fullStr | Immune escape and resistance to immunotherapy in mismatch repair deficient tumors |
title_full_unstemmed | Immune escape and resistance to immunotherapy in mismatch repair deficient tumors |
title_short | Immune escape and resistance to immunotherapy in mismatch repair deficient tumors |
title_sort | immune escape and resistance to immunotherapy in mismatch repair deficient tumors |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10363668/ https://www.ncbi.nlm.nih.gov/pubmed/37492581 http://dx.doi.org/10.3389/fimmu.2023.1210164 |
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