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

We report differential effects of mutations in genes of the homologous recombination (HR) pathway on response after ICB administration in mouse and human tumors, and show that truncating mutations in BRCA2 are associated with superior response to ICB compared to BRCA1-deficient tumors. Immunogenomic analyses demonstrated that mutations in BRCA1 and BRCA2 differentially modulate the tumor-immune microenvironment, with gene expression programs related to both adaptive and innate immune pathways enriched in BRCA2-deficient tumors. Single-cell RNA sequencing further revealed distinct T cell, NK, macrophage, and dendritic cell populations enriched in BRCA2 mutant tumors relative to BRCA1-deficient tumors. Bulk RNA-sequencing from immunotherapy-naïve and immunotherapy-treated mouse 4T1 parental, Brca1 mutant, and Brca2 mutant tumors. Single cell RNA-sequencing from immunotherapy-naïve 4T1 parental, Brca1 mutant, and Brca2 mutant tumors