PROJECT SUMMARY It has been shown that variation in cancer risk is influenced by mutations that may be inherited, caused by environmental factors such as smoking and ultraviolet exposure, or resulting from random DNA replication errors. Here we propose a novel factor in cancer risk, which is related to the genetic diversity of the immune system across humans and its ability to detect and eliminate early cancers. Immunosurveillance is the concept that the immune system acts as a surveillance system to detect and destroy neoplastic cells before they progress to a detectable malignant cancer. This process relies on T cells, which recognize tumor mutation-derived neoantigens presented by the human leukocyte antigen (HLA) molecules on the cell surface, resulting in tumor- killing. While HLA genes are among the most polymorphic genes in vertebrates, including humans, and are associated with several infectious diseases and can also increase the risk for autoimmunity, our preliminary analysis suggests HLA diversity influences cancer risk. The goal of this proposed research is to study the contribution of immunogenetics on the efficiency of tumor immune surveillance and its ultimate effect on cancer risk. Our preliminary analysis demonstrates an association between HLA homozygosity and increased risk of cancer in lung cancer. Using large prospective cohorts of individuals with deep genetic and phenotypic data, we will investigate the relationship of HLA diversity and lung and melanoma cancer risk and the interaction of HLA immunogenetics with environmental risk factors. A murine carcinogen induced lung cancer model will offer validation of causality as well as mechanistic insights for therapeutic targets. The insights gained from these studies will potentially improve predictive cancer risk models in germline carriers and suggest strategies for immune-mediated cancer prevention.