To investigate the relationship between DNA damage repair deficiency (DDR-d) and response to immunotherapy, Qing et al. evaluated the association between alterations in DDR genes (germline/somatic mutations and methylation) with tumor neoantigens and immune infiltrates in 10,080 cancers from 32 cancer types. Mutations in homologous recombination genes were very frequently associated with higher TMB and neoantigen loads, and somatic DDR-ds were associated with tumor immune infiltration, higher neoantigen load, and better survival after immunotherapy, but these effects varied by cancer type. MLH1 deficiency classified neoantigen-high tumors for higher immunogenicity.
Contributed by Shishir Pant
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.
Author Info: (1) Breast Medical Oncology, Yale School of Medicine, New Haven, CT 06511, USA. (2) Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at
Author Info: (1) Breast Medical Oncology, Yale School of Medicine, New Haven, CT 06511, USA. (2) Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (3) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (4) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (5) Breast Medical Oncology, Yale School of Medicine, New Haven, CT 06511, USA. Department of Data Science and Engineering, Silesian University of Technology, Gliwice, Poland. (6) Breast Medical Oncology, Yale School of Medicine, New Haven, CT 06511, USA. (7) Department of Genetics and Genomic Sciences, Center for Transformative Disease Modeling, Tisch Cancer Institute, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
