Open AccessMutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy
Author(s) -
Robert M. Samstein,
Chirag Krishna,
Xiaoxiao Ma,
Xin Pei,
Ken Wing Lee,
Vladimir Makarov,
Fengshen Kuo,
Jonathan H. Chung,
Raghvendra M. Srivastava,
Tanaya A. Purohit,
Douglas R. Hoen,
Rajarsi Mandal,
Jeremy Setton,
Wei Wu,
Rachna Shah,
Besnik Qeriqi,
Qing Chang,
Sviatoslav M. Kendall,
Lior Z. Braunstein,
Britta Weigelt,
Pedro Blecua,
Luc G.T. Morris,
Diana Mandelker,
Jorge S. ReisFilho,
Elisa de Stanchina,
Simon N. Powell,
Timothy A. Chan,
Nadeem Riaz
Publication year - 2020
Publication title -
nature cancer
Language(s) - English
Resource type - Journals
ISSN - 2662-1347
DOI - 10.1038/s43018-020-00139-8
Subject(s) - biology , immunotherapy , immune checkpoint , blockade , tumor microenvironment , cancer immunotherapy , cancer research , homologous recombination , mutation , gene , immune system , immunology , genetics , receptor
Immune checkpoint blockade (ICB) has improved outcomes for patients with advanced cancer, but the determinants of response remain poorly understood. Here we report differential effects of mutations in the homologous recombination genes BRCA1 and BRCA2 on response to ICB in mouse and human tumors, and further show that truncating mutations in BRCA2 are associated with superior response compared to those in BRCA1. Mutations in BRCA1 and BRCA2 result in distinct mutational landscapes and differentially modulate the tumor-immune microenvironment, with gene expression programs related to both adaptive and innate immunity enriched in BRCA2-deficient tumors. Single-cell RNA sequencing further revealed distinct T cell, natural killer, macrophage, and dendritic cell populations enriched in BRCA2-deficient tumors. Taken together, our findings reveal the divergent effects of BRCA1 and BRCA2-deficiency on ICB outcome, and have significant implications for elucidating the genetic and microenvironmental determinants of response to immunotherapy.