破译肿瘤微环境（TME）的组成对于理解肿瘤发生和设计免疫疗法至关重要。在本研究中，我们使用单细胞和批量 RNA 测序数据绘制了遗传效应对细胞类型比例的影响，从癌症基因组图谱中识别出 23 种癌症类型的 3,494 个免疫数量性状位点 (immunQTL)。功能注释揭示了调节潜力，我们进一步指定了调节 TME 组成的 1,668 个基因。我们通过整合欧洲和中国结直肠癌（CRC）样本的数据构建了组合的免疫QTL图谱。结合了这些免疫 QTL 和全基因组关联研究的多基因风险评分在 447,495 名多种族个体的 CRC 风险分层中表现出色。通过大规模人群队列研究，我们发现immunQTL rs1360948与CRC风险和预后相关。从机制上讲，rs1360948-G-等位基因会增加 CCL2 的表达，招募可对 CRC 进展发挥免疫抑制作用的调节性 T 细胞。阻断 CCL2-CCR2 轴可增强抗程序性细胞死亡蛋白 1 配体治疗。最后，我们建立了一个数据库 (CancerlmmunityQTL2) 来为研究界服务并增进我们对癌症发病机制中免疫基因组相互作用的理解。© 2024。Springer Nature America, Inc.

Deciphering the composition of the tumor microenvironment (TME) is critical for understanding tumorigenesis and to design immunotherapies. In the present study, we mapped genetic effects on cell-type proportions using single-cell and bulk RNA sequencing data, identifying 3,494 immunity quantitative trait loci (immunQTLs) across 23 cancer types from The Cancer Genome Atlas. Functional annotation revealed regulatory potential and we further assigned 1,668 genes that regulate TME composition. We constructed a combined immunQTL map by integrating data from European and Chinese colorectal cancer (CRC) samples. A polygenic risk score that incorporates these immunQTLs and hits on a genome-wide association study outperformed in CRC risk stratification within 447,495 multiethnic individuals. Using large-scale population cohorts, we identified that the immunQTL rs1360948 is associated with CRC risk and prognosis. Mechanistically, the rs1360948-G-allele increases CCL2 expression, recruiting regulatory T cells that can exert immunosuppressive effects on CRC progression. Blocking the CCL2-CCR2 axis enhanced anti-programmed cell death protein 1 ligand therapy. Finally, we have established a database (CancerlmmunityQTL2) to serve the research community and advance our understanding of immunogenomic interactions in cancer pathogenesis.© 2024. Springer Nature America, Inc.