近日，武汉大学缪小平等研究人员合作绘制出肿瘤微环境细胞组成的遗传效应图谱。2024年9月2日，《自然—免疫学》杂志在线发表了这项成果。

研究人员利用单细胞和整体RNA测序数据绘制了遗传效应对细胞类型比例的影响，识别出来自癌症基因组图谱（The Cancer Genome Atlas）中的23种癌症类型的3494个免疫量化性状位点（immunQTL）。功能注释揭示了这些位点的调控潜力，并进一步确定了1668个调节肿瘤微环境（TME）组成的基因。

研究人员通过整合来自欧洲和中国结直肠癌（CRC）样本的数据，构建了一个综合的免疫QTL图谱。包含这些免疫QTL和全基因组关联研究中的击中位点的多基因风险评分，在447495名多民族个体中，表现出优于CRC风险分层的能力。利用大规模人群队列，研究人员发现免疫QTL rs1360948与CRC风险和预后相关。

从机制上讲，rs1360948-G等位基因增加了CCL2的表达，招募了能够对CRC进展产生免疫抑制效应的调节性T细胞。阻断CCL2–CCR2轴增强了抗程序性死亡蛋白1配体疗法的效果。最后，研究人员建立了一个数据库（CancerlmmunityQTL2），以服务于研究社区并推进人们对癌症发病机制中免疫基因组相互作用的理解。

据悉，揭示TME组成对于理解肿瘤发生和设计免疫疗法至关重要。

附：英文原文

Title: An atlas of genetic effects on cellular composition of the tumor microenvironment

Author: Cai, Yimin, Lu, Zequn, Chen, Can, Zhu, Ying, Chen, Zhirui, Wu, Zuyou, Peng, Jingyi, Zhu, Xuanyu, Liu, Ziying, Li, Bin, Zhang, Ming, Huang, Jinyu, Li, Yanmin, Liu, Yizhuo, Ma, Qianying, He, Chunyi, Chen, Shuoni, Tian, Wen, Fan, Linyun, Ning, Caibo, Geng, Hui, Xu, Bin, Li, Haijie, Zhu, Xu, Fang, Jun, Wang, Xiaoyang, Zhang, Shaokai, Jin, Meng, Huang, Chaoqun, Yang, Xiaojun, Tian, Jianbo, Miao, Xiaoping

Issue&Volume: 2024-09-02

Abstract: 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.

DOI: 10.1038/s41590-024-01945-3

Source: https://www.nature.com/articles/s41590-024-01945-3