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Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer
Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are micr...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068608/ https://www.ncbi.nlm.nih.gov/pubmed/32210966 http://dx.doi.org/10.3389/fimmu.2020.00369 |
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author | Picard, Emilie Verschoor, Chris P. Ma, Grace W. Pawelec, Graham |
author_facet | Picard, Emilie Verschoor, Chris P. Ma, Grace W. Pawelec, Graham |
author_sort | Picard, Emilie |
collection | PubMed |
description | Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option. |
format | Online Article Text |
id | pubmed-7068608 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-70686082020-03-24 Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer Picard, Emilie Verschoor, Chris P. Ma, Grace W. Pawelec, Graham Front Immunol Immunology Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option. Frontiers Media S.A. 2020-03-06 /pmc/articles/PMC7068608/ /pubmed/32210966 http://dx.doi.org/10.3389/fimmu.2020.00369 Text en Copyright © 2020 Picard, Verschoor, Ma and Pawelec. http://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 Picard, Emilie Verschoor, Chris P. Ma, Grace W. Pawelec, Graham Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer |
title | Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer |
title_full | Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer |
title_fullStr | Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer |
title_full_unstemmed | Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer |
title_short | Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer |
title_sort | relationships between immune landscapes, genetic subtypes and responses to immunotherapy in colorectal cancer |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068608/ https://www.ncbi.nlm.nih.gov/pubmed/32210966 http://dx.doi.org/10.3389/fimmu.2020.00369 |
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