Mutations in
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
entrez:
9
4
2021
pubmed:
10
4
2021
medline:
10
4
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33834176
doi: 10.1038/s43018-020-00139-8
pmc: PMC8023400
mid: NIHMS1682221
pii: 10.1038/s43018-020-00139-8
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
BRCA2 Protein
0
BRCA2 protein, human
0
Immune Checkpoint Inhibitors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
1188-1203Subventions
Organisme : NIH HHS
ID : U54 OD020355
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA205426
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA232097
Pays : United States
Organisme : NIH HHS
ID : DP5 OD028171
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009685
Pays : United States
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