In recent years, immunotherapies have transformed the treatment landscape for patients with advanced lung cancer and melanoma, leading to durable responses in a subset of cases but rarely curing patients of the disease. These treatments, in particular, immune checkpoint inhibitors (ICIs) that block inhibitory signals on T- cells, like programmed cell death protein 1 (PD-1), lead to responses in 15-20% of unselected patients with non- small cell lung cancer (NSCLC) and up to 60% of melanoma patients. On the basis of these studies several immune checkpoint inhibitors have been FDA-approved for the treatment of metastatic melanoma and advanced NSCLC. Increasing numbers of patients are receiving these therapies, however many initially benefit from them and eventually develop drug-resistant disease. To date, there is little knowledge of the molecular and cellular mechanisms that underlie acquired resistance to ICIs. As a result, effective therapeutic strategies to treat patients with ICI-resistant disease are lacking. The long-term goal of the research proposed here is to provide mechanistic insight into acquired resistance to ICIs in lung cancer and melanoma and thus contribute to the development of evidence-based approaches to overcome ICI resistance. Our group has pioneered approaches to study mechanisms of acquired resistance to ICIs in lung cancer. Moreover, we have optimized methods for the in vivo analysis of resistance to ICIs in immunocompetent lung cancer and melanoma mouse models. These studies have revealed that impaired MHC I antigen presentation plays a central role in conferring acquired resistance to ICIs. We hypothesize that multiple different mechanisms including genetic alterations, epigenetic changes and altered immune signaling pathways can lead to downregulation of antigen presentation causing resistance to ICIs. Further, we posit that knowledge of these mechanisms and their immunological consequences can be used to devise therapeutic strategies to overcome ICI-resistance. Thus, we propose to leverage our unique experimental systems to: 1) Determine how defects in MHC I antigen presentation in ICI-resistant tumors affect the immune landscape, especially natural killer (NK) cell function, 2) Elucidate the genetic processes that lead to impaired MHC I antigen presentation in ICI-resistant lung cancers and 3) Determine whether epigenetic silencing of genes encoding MHC I APM components can lead to resistance to ICIs. Together, these studies will provide us with a comprehensive understanding of the mechanisms that underlie defects in MHC I antigen presentation in lung tumors and melanomas resistant to immune checkpoint inhibitors and will set the stage for potential new approaches to overcome this resistance.