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.

免疫检查点阻断 (ICB) 改善了晚期癌症患者的预后，但反应的决定因素仍然知之甚少。在这里，我们报告了同源重组基因BRCA1和BRCA2突变对小鼠和人类肿瘤对 ICB 反应的不同影响，并进一步表明，与BRCA1相比， BRCA2中的截断突变与更好的反应有关。BRCA1和BRCA2的突变导致不同的突变景观并差异调节肿瘤免疫微环境，其中与适应性和先天免疫相关的基因表达程序富含BRCA2- 缺陷型肿瘤。单细胞 RNA 测序进一步揭示了富含BRCA2缺陷肿瘤的不同 T 细胞、自然杀伤细胞、巨噬细胞和树突细胞群。总之，我们的研究结果揭示了BRCA1和BRCA2缺乏对 ICB 结果的不同影响，并对阐明免疫治疗反应的遗传和微环境决定因素具有重要意义。