The use of immunotherapy can result in significant responses in a subset of aggressive, advanced kidney cancers. However, only a minority of patients with this disease benefit from this potentially toxic therapy. There is a real need to figure out which patients are most likely to benefit from immunotherapy and also develop methods to increase the overall effectiveness. The studies in this proposal will test the novel hypothesis that abnormal expression of old "genomic fossils" called endogenous retroviruses, which are part of what is considered "junk DNA," in kidney cancer is strongly associated with response to immune checkpoint therapy. This will be done by analysis of human kidney cancer specimens and by doing experiments in human kidney cancer cell models. If successful, this project will lead to tests that may in the future determine which patients with kidney cancer will benefit most from immune checkpoint therapy. Moreover, this research may also identify rational combination therapies that may increase response rates to immunotherapy. The ultimate aim is to improve the effectiveness of immunotherapy and ultimately improve the survival of men and women affected by this aggressive cancer. This application directly addresses the following KCRP areas of interest: chromatin and gene regulation and microenvironment and immunology (in basic/translational science); immunotherapy (in treatments/survivorship).