Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy Journal Article
| Authors: | Samstein, R. M.; Krishna, C.; Ma, X.; Pei, X.; Lee, K. W.; Makarov, V.; Kuo, F.; Chung, J.; Srivastava, R. M.; Purohit, T. A.; Hoen, D. R.; Mandal, R.; Setton, J.; Wu, W.; Shah, R.; Qeriqi, B.; Chang, Q.; Kendall, S.; Braunstein, L.; Weigelt, B.; Blecua Carrillo Albornoz, P.; Morris, L. G. T.; Mandelker, D. L.; Reis-Filho, J. S.; de Stanchina, E.; Powell, S. N.; Chan, T. A.; Riaz, N. |
| Article Title: | Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy |
| 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 important implications for elucidating the genetic and microenvironmental determinants of response to immunotherapy. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. part of Springer Nature. |
| Keywords: | controlled study; human tissue; gene mutation; overall survival; single nucleotide polymorphism; somatic mutation; nonhuman; flow cytometry; genetic analysis; cd8+ t lymphocyte; animal cell; mouse; phenotype; animal tissue; cell viability; cancer immunotherapy; breast cancer; gene expression; dendritic cell; prevalence; animal experiment; animal model; cytotoxicity; immunofluorescence; cell population; angiogenesis; brca1 protein; brca2 protein; microarray analysis; microsatellite instability; western blotting; cell cycle checkpoint; innate immunity; real time polymerase chain reaction; inflammatory infiltrate; estrogen receptor; progesterone receptor; cytotoxic t lymphocyte antigen 4; macrophage; immunosuppressive treatment; hermes antigen; karyotyping; olaparib; rna sequence; tumor microenvironment; copy number variation; high mobility group b1 protein; cd47 antigen; epithelial derived neutrophil activating factor 78; recombination repair; human; female; priority journal; article; whole exome sequencing; crispr-cas9 system; immunogenomics; single cell rna seq |
| Journal Title: | Nature Cancer |
| Volume: | 1 |
| Issue: | 12 |
| ISSN: | 2662-1347 |
| Publisher: | Nature Research |
| Date Published: | 2020-12-01 |
| Start Page: | 1188 |
| End Page: | 1203 |
| Language: | English |
| DOI: | 10.1038/s43018-020-00139-8 |
| PROVIDER: | scopus |
| PMCID: | PMC8023400 |
| PUBMED: | 33834176 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 January 2021 -- Source: Scopus |
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