Immunogenetics of cancer risk: an emerging role for HLA class II 2623

Abstract Description Host immune system contribution to cancer risk remains poorly understood and necessary to improve cancer prevention strategies. Detection of foreign antigens presented on MHC molecules is critical for immune recognition. Since each HLA allele can bind a specific set of antigens, HLA heterozygosity confers a selective advantage against disease, which has been shown in the context of viral disease and immunotherapy. Using longitudinal clinical and genetic information from over 600,000 individuals in the UK Biobank and FinnGen, we show that germline heterozygosity at HLA-II loci, but not HLA-I loci, is associated with decreased risk of lung cancer among smokers. Strikingly, this effect is independent of a genome-wide polygenic risk score (PRS) and HLA-II homozygosity increases lifetime risk of lung cancer. We also show that loss of HLA-II on tumor cells is as prevalent in non-small cell lung cancer as loss of HLA-I, a known mechanism of immune escape, with preferential loss of alleles with larger neopeptide repertoires, highlighting the importance of HLA-II expression on epithelial cells. Ongoing studies in murine models of carcinogen-induced lung cancer are aimed at dissecting the relative roles of MHC-II on epithelial cells and immune cells as well as the overall importance of CD4 T cells in tumor immunosurveillance. These findings deepen our understanding of the role of the immune system in cancer risk and will inform immune-directed cancer prevention strategies. Funding Sources NIH/NCI R01; Mathers Foundation Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)