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首页> 外文期刊>Nature cancer. >Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy
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Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy

机译：BRCA1和BRCA2的突变影响不同肿瘤微环境和应对检查点封锁免疫疗法

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摘要

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.
机译：免疫检查点封锁(ICB)得到了改善结果晚期癌症患者,但是反应的决定因素仍不佳理解。同源重组的突变基因BRCA1和BRCA2在鼠标应对银行独立委员会和人类肿瘤,并进一步说明删除BRCA2突变有关优越的响应相比BRCA1。BRCA1和BRCA2的突变导致截然不同的突变的风景和不同的调节肿瘤免疫微环境,基因自适应和相关表达式的程序先天免疫在BRCA2-deficient丰富肿瘤。显示不同的t细胞、自然杀伤巨噬细胞和树突状细胞数量富含BRCA2-deficient肿瘤。在一起,我们的研究结果揭示了发散BRCA1和BRCA2缺乏对银行独立委员会的影响结果,具有重要意义阐明基因和微环境免疫治疗反应的决定因素。

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