@article{00b534fcf803453fa364e6ad13ca293d,
title = "Diverse immune response of DNA damage repair-deficient tumors",
abstract = "Tumors with DNA damage repair (DDR) deficiency accumulate genomic alterations that may serve as neoantigens and increase sensitivity to immune checkpoint inhibitor. However, over half of DDR-deficient tumors are refractory to immunotherapy, and it remains unclear which mutations may promote immunogenicity in which cancer types. We integrate deleterious somatic and germline mutations and methylation data of DDR genes in 10,080 cancers representing 32 cancer types and evaluate the associations of these alterations with tumor neoantigens and immune infiltrates. Our analyses identify DDR pathway mutations that are associated with higher neoantigen loads, adaptive immune markers, and survival outcomes of immune checkpoint inhibitor-treated animal models and patients. Different immune phenotypes are associated with distinct types of DDR deficiency, depending on the cancer type context. The comprehensive catalog of immune response-associated DDR deficiency may explain variations in immunotherapy outcomes across DDR-deficient cancers and facilitate the development of genomic biomarkers for immunotherapy.",
keywords = "DNA damage repair deficiency, germline variant, immune checkpoint inhibitor, immune infiltrate, immunogenicity, methylation, mismatch repair, neoantigen, somatic mutations, tumor mutation burden",
author = "Tao Qing and Tomi Jun and Lindblad, {Katherine E.} and Amaia Lujambio and Michal Marczyk and Lajos Pusztai and Huang, {Kuan lin}",
note = "Funding Information: L.P. has received consulting fees and honoraria from Pfizer, AstraZeneca, Merck, Novartis, Bristol-Myers Squibb, Genentech, Eisai, Pieris, Immunomedics, Seattle Genetics, Clovis, Syndax, H3Bio, and Daiichi. A.L. has received grant support from Pfizer and Genentech for unrelated projects. The rest of the authors declare no competing interests. Funding Information: The authors wish to acknowledge the participating patients and family who generously contributed to the datasets. The work is supported by NIH NCI R37CA230636 and NIGMS R35GM138113 from the Icahn School of Medicine at Mount Sinai, the Breast Cancer Research Foundation (Investigator award BCRF 19-133), and the Susan G. Komen Foundation (grant no. SAC160076) from Yale Cancer Center. K.-l.H. and T.Q. conceived the research and designed the analyses. T.Q. conducted the TCGA analyses and T.J. conducted the patient-cohort survival analyses. M.M. helped with the statistical method. K.E.L. and A.L. conducted the in vivo experiments. L.P. and K.-l.H. supervised the study. T.Q. K.-l.H. and L.P. wrote the manuscript. All of the authors read, edited, and approved the manuscript. L.P. has received consulting fees and honoraria from Pfizer, AstraZeneca, Merck, Novartis, Bristol-Myers Squibb, Genentech, Eisai, Pieris, Immunomedics, Seattle Genetics, Clovis, Syndax, H3Bio, and Daiichi. A.L. has received grant support from Pfizer and Genentech for unrelated projects. The rest of the authors declare no competing interests. Funding Information: The authors wish to acknowledge the participating patients and family who generously contributed to the datasets. The work is supported by NIH NCI R37CA230636 and NIGMS R35GM138113 from the Icahn School of Medicine at Mount Sinai , the Breast Cancer Research Foundation (Investigator award BCRF 19-133 ), and the Susan G. Komen Foundation (grant no. SAC160076 ) from Yale Cancer Center . Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = may,
day = "18",
doi = "10.1016/j.xcrm.2021.100276",
language = "English",
volume = "2",
journal = "Cell Reports Medicine",
issn = "2666-3791",
publisher = "Cell Press",
number = "5",
}