Understanding the contribution of the host’s genetic background to cancer immunity may lead to improved stratification for immunotherapy and to the identification of novel therapeutic targets. We investigated the effect of common and rare germline variants on 139 well-defined immune traits in ∼9000 cancer patients enrolled in TCGA. High heritability was observed for estimates of NK cell and T cell subset infiltration and for interferon signaling. Common variants of IFIH1, TMEM173 (STING1), and TMEM108 were associated with differential interferon signaling and variants mapping to RBL1 correlated with T cell subset abundance. Pathogenic or likely pathogenic variants in BRCA1 and in genes involved in telomere stabilization and Wnt-β-catenin also acted as immune modulators. Our findings provide evidence for the impact of germline genetics on the composition and functional orientation of the tumor immune microenvironment. The curated datasets, variants, and genes identified provide a resource toward further understanding of tumor-immune interactions.

了解宿主遗传背景对癌症免疫的贡献可能会改善免疫治疗的分层并确定新的治疗靶点。我们研究了常见和罕见的种系变异对 TCGA 入组的约 9000 名癌症患者中 139 种明确免疫特征的影响。对于 NK 细胞和 T 细胞亚群浸润的估计以及干扰素信号传导，观察到高遗传性。IFIH1、TMEM173 (STING1)和TMEM108的常见变体与差异干扰素信号传导相关，映射到RBL1的变体与 T 细胞亚群丰度相关。BRCA1中的致病性或可能致病性变异在与端粒稳定有关的基因中，Wnt-β-catenin 也起到免疫调节剂的作用。我们的研究结果为种系遗传学对肿瘤免疫微环境的组成和功能方向的影响提供了证据。确定的精选数据集、变体和基因为进一步了解肿瘤-免疫相互作用提供了资源。