Anti-tumor immune responses depend on T cell recognition of tumor antigens in the context of major histocompatibility complex (MHC) proteins to destroy tumors. While the MHC class I antigen presentation pathway in melanoma cells has a well-established role in immune-mediated destruction of tumors, the function of the MHC class II antigen presentation pathway in melanoma cells is not well understood. The goal of this proposal is to determine the function of MHC class II and the MHC class II antigen processing enzyme, GILT, in melanoma cells in regulating the anti-tumor immune response and response to immunotherapy. Preliminary results from the laboratory of the PI revealed that the MHC class II antigen presentation pathway and GILT, an enzyme involved in MHC class II antigen processing, are associated with improved survival in melanoma. Recent data from other groups show that induction of MHC class II expression on melanoma cells is associated with improved response to immune checkpoint blockade with anti-PD-1 in retrospective analyses. Immune checkpoint blockade with anti-PD-1 is being used to treat a rapidly growing number of cancer types and patients. Yet, the challenge remains that at least 60% and 25% of melanoma patients exhibit primary and acquired resistance to this therapy, respectively. The central hypothesis of this proposal is that the MHC class II antigen presentation pathway in melanoma cells enhances T cell-mediated destruction of tumors and improves the response to immune checkpoint blockade. To test this hypothesis clinically-relevant, immunogenic mouse models of melanoma will be employed to determine the role of GILT and MHC class II in melanoma cells on regulating the anti-tumor immune response and response to immunotherapy. This research team will determine the immunomodulatory effects of GILT and MHC class II expression in melanoma cells and identify immune cell types required for the modulation of tumor growth. Impact: New knowledge gained from the completion of these studies is anticipated to lead to improved patient outcomes. Determining the biological basis for MHC class II pathway members in the anti-tumor immune response and response to immunotherapy is expected to 1) identify novel causal determinants of immunologically hot vs. cold tumors, 2) provide support for a personalized medicine approach to optimize immunotherapy efficacy and limit side effects, and 3) define a novel pathway controlling anti-tumor immune responses that can be manipulated to augment treatment efficacy. The results of these studies are anticipated to be broadly applicable, as many cancers express MHC class II and all cancer types share the challenge of resistance to immunotherapy.