4.5 Article

Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy

Journal

NATURE CANCER
Volume 1, Issue 12, Pages 1188-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s43018-020-00139-8

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Funding

  1. Breast Cancer Research Foundation
  2. National Institutes of Health (NIH)/National Cancer Institute Cancer Center Support Grant [P30 CA008748]
  3. Pershing Square Sohn Cancer Research grant
  4. PaineWebber Chair
  5. Stand Up 2 Cancer
  6. NIH [R01 CA205426, R35 CA232097, U54 OD020355]
  7. STARR Cancer Consortium
  8. AACR Translational Immunology
  9. NIH Director's Early Independence Award [DP5-OD028171]
  10. Burroughs Wellcome Fund Career Award for Medical Scientists
  11. Precision Immunotherapy Kidney Cancer Fund
  12. Frederick Adler Fund

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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.

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