Common Genetic Variants Influence The Composition Of The Tumor Immune Microenvironment And Host Anti-Tumor Responses.

Abstract Developing effective therapies to intervene in the tumor immune evasion process is a challenge further complicated by interindividual variability in tumor-host immunological interactions. Germline variation is a major component of interindividual variability usually studied by large-scale genome-wide association studies (GWAS) in the context of disease risk; yet, there is still a gap in our understanding of germline variation specifically in the tumor immune microenvironment. To address this, we systematically characterized the immune effects of germline genetic polymorphisms across 33 human cancer types in the TCGA. Immune microenvironment phenotypes include immune infiltration levels as calculated by CIBERSORTx and expression of immunomodulator genes obtained through literature curation. PCA analysis reduced dimensionality of immune phenotypes, with macrophage regulation and EP300/Proteosome expression mediating most variability amongst individuals. We identified 482 SNP-immune gene associations, where a subset of SNPs affected multiple immune phenotypes. Using cell-type and epigenetic analyses, we further characterized immune microenvironment variants to act through macrophage and dendritic cell-specific manners and alter immune-cell specific epigenetic regions. Through burden analysis, we found several of these variants interact to have stronger immune microenvironment effects. Lastly, using ICB-trial cohorts, we found several variants affecting LILRB2, LILRB4, LAIR1, CCBL2, and CTSW modulate response to immune checkpoint blockade. Our results provide better understanding of how germline variation modifies tumor immune microenvironment dynamics and will set up further studies to identify predictive biomarkers of the tumor immune microenvironment. Citation Format: Meghana Pagadala, Hyo Kim, Andrea Castro, Cristian Gonzalez-Colin, Victoria Wu, Steven Cao, Benjamin Schmiedel, Rany Salem, Silvio Gutkind, Wes Thompson, Vijayanand Pandurangan, Hannah Carter. Common genetic variants influence the composition of the tumor immune microenvironment and host anti-tumor responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 828.