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和 中的突变差异影响肿瘤微环境和对检查点封锁免疫治疗的反应。

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

机构信息

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Department of Radiation Oncology, Mount Sinai Hospital, New York, NY, USA.

出版信息

Nat Cancer. 2021 Dec;1(12):1188-1203. doi: 10.1038/s43018-020-00139-8. Epub 2020 Nov 16.

DOI:10.1038/s43018-020-00139-8
PMID:33834176
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8023400/
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 significant implications for elucidating the genetic and microenvironmental determinants of response to immunotherapy.

摘要

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知之甚少。在这里，我们报告同源重组基因 BRCA1 和 BRCA2 中的突变对小鼠和人类肿瘤对 ICB 反应的差异影响，并进一步表明 BRCA2 中的截断突变与 BRCA1 中的突变相比与更好的反应相关。BRCA1 和 BRCA2 中的突变导致不同的突变景观，并以不同的方式调节肿瘤免疫微环境，与适应性和先天免疫相关的基因表达程序在 BRCA2 缺陷型肿瘤中富集。单细胞 RNA 测序进一步揭示了 BRCA2 缺陷型肿瘤中富集的不同 T 细胞、自然杀伤细胞、巨噬细胞和树突状细胞群体。总之，我们的研究结果揭示了 BRCA1 和 BRCA2 缺陷对 ICB 结果的不同影响，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。

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