Cargando…
Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma
Mutations in DNA repair genes lead to increased genomic instability and mutation frequency. These mutations represent potential biomarkers for cancer immunotherapy efficacy, as high tumor mutational burden has been associated with increased neo-antigens and tumor infiltrating lymphocytes. While mism...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814272/ https://www.ncbi.nlm.nih.gov/pubmed/29487705 http://dx.doi.org/10.18632/oncotarget.23742 |
_version_ | 1783300315514142720 |
---|---|
author | Chae, Young Kwang Anker, Jonathan F. Bais, Preeti Namburi, Sandeep Giles, Francis J. Chuang, Jeffrey H. |
author_facet | Chae, Young Kwang Anker, Jonathan F. Bais, Preeti Namburi, Sandeep Giles, Francis J. Chuang, Jeffrey H. |
author_sort | Chae, Young Kwang |
collection | PubMed |
description | Mutations in DNA repair genes lead to increased genomic instability and mutation frequency. These mutations represent potential biomarkers for cancer immunotherapy efficacy, as high tumor mutational burden has been associated with increased neo-antigens and tumor infiltrating lymphocytes. While mismatch repair mutations have successfully predicted response to anti-PD-1 therapy in colorectal and other cancers, they have not yet been tested for lung cancer, and few have investigated genes from other DNA repair pathways. We utilized TCGA samples to comprehensively immunophenotype lung tumors and analyze the links between DNA repair mutations, neo-antigen and total mutational burden, and tumor immune infiltration. Overall, 73% of lung tumors contained infiltration by at least one T cell subset, with high mutational burden tumors containing significantly increased infiltration by activated CD4 and CD8 T cells. Further, mutations in mismatch repair genes, homologous recombination genes, or POLE accurately predicted increased tumor mutational burden, neo-antigen load, and T cell infiltration. Finally, neo-antigen load correlated with expression of M1-polarized macrophage genes, PD-1, PD-L1, IFNγ, GZMB, and FASLG, among other immune-related genes. Overall, after defining the immune infiltrate in lung tumors, we demonstrate the potential value of utilizing gene mutations from multiple DNA repair pathways as biomarkers for lung cancer immunotherapy. |
format | Online Article Text |
id | pubmed-5814272 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-58142722018-02-27 Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma Chae, Young Kwang Anker, Jonathan F. Bais, Preeti Namburi, Sandeep Giles, Francis J. Chuang, Jeffrey H. Oncotarget Research Paper Mutations in DNA repair genes lead to increased genomic instability and mutation frequency. These mutations represent potential biomarkers for cancer immunotherapy efficacy, as high tumor mutational burden has been associated with increased neo-antigens and tumor infiltrating lymphocytes. While mismatch repair mutations have successfully predicted response to anti-PD-1 therapy in colorectal and other cancers, they have not yet been tested for lung cancer, and few have investigated genes from other DNA repair pathways. We utilized TCGA samples to comprehensively immunophenotype lung tumors and analyze the links between DNA repair mutations, neo-antigen and total mutational burden, and tumor immune infiltration. Overall, 73% of lung tumors contained infiltration by at least one T cell subset, with high mutational burden tumors containing significantly increased infiltration by activated CD4 and CD8 T cells. Further, mutations in mismatch repair genes, homologous recombination genes, or POLE accurately predicted increased tumor mutational burden, neo-antigen load, and T cell infiltration. Finally, neo-antigen load correlated with expression of M1-polarized macrophage genes, PD-1, PD-L1, IFNγ, GZMB, and FASLG, among other immune-related genes. Overall, after defining the immune infiltrate in lung tumors, we demonstrate the potential value of utilizing gene mutations from multiple DNA repair pathways as biomarkers for lung cancer immunotherapy. Impact Journals LLC 2017-12-15 /pmc/articles/PMC5814272/ /pubmed/29487705 http://dx.doi.org/10.18632/oncotarget.23742 Text en Copyright: © 2018 Chae et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper Chae, Young Kwang Anker, Jonathan F. Bais, Preeti Namburi, Sandeep Giles, Francis J. Chuang, Jeffrey H. Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma |
title | Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma |
title_full | Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma |
title_fullStr | Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma |
title_full_unstemmed | Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma |
title_short | Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma |
title_sort | mutations in dna repair genes are associated with increased neo-antigen load and activated t cell infiltration in lung adenocarcinoma |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814272/ https://www.ncbi.nlm.nih.gov/pubmed/29487705 http://dx.doi.org/10.18632/oncotarget.23742 |
work_keys_str_mv | AT chaeyoungkwang mutationsindnarepairgenesareassociatedwithincreasedneoantigenloadandactivatedtcellinfiltrationinlungadenocarcinoma AT ankerjonathanf mutationsindnarepairgenesareassociatedwithincreasedneoantigenloadandactivatedtcellinfiltrationinlungadenocarcinoma AT baispreeti mutationsindnarepairgenesareassociatedwithincreasedneoantigenloadandactivatedtcellinfiltrationinlungadenocarcinoma AT namburisandeep mutationsindnarepairgenesareassociatedwithincreasedneoantigenloadandactivatedtcellinfiltrationinlungadenocarcinoma AT gilesfrancisj mutationsindnarepairgenesareassociatedwithincreasedneoantigenloadandactivatedtcellinfiltrationinlungadenocarcinoma AT chuangjeffreyh mutationsindnarepairgenesareassociatedwithincreasedneoantigenloadandactivatedtcellinfiltrationinlungadenocarcinoma |