| Literature DB >> 33834176 |
Robert M Samstein1,2,3, Chirag Krishna4, Xiaoxiao Ma5, Xin Pei1, Ken-Wing Lee5, Vladimir Makarov6, Fengshen Kuo6, Jonathan Chung3, Raghvendra M Srivastava6, Tanaya A Purohit6, Douglas R Hoen6, Rajarsi Mandal5, Jeremy Setton1, Wei Wu5, Rachna Shah1, Besnik Qeriqi7, Qing Chang7, Sviatoslav Kendall6, Lior Braunstein1, Britta Weigelt8, Pedro Blecua Carrillo Albornoz1,9, Luc G T Morris5,6,10, Diana L Mandelker8, Jorge S Reis-Filho8, Elisa de Stanchina7, Simon N Powell1, Timothy A Chan11,12,13,14, Nadeem Riaz15,16,17.
Abstract
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.Entities:
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Year: 2020 PMID： 33834176 PMCID： PMC8023400 DOI： 10.1038/s43018-020-00139-8
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347