PROJECT SUMMARY/ABSTRACT Melanoma is the most lethal type of skin cancer. About 50% of patients with metastatic melanoma have a meaningful response to treatment with immunotherapy, of which some develop a durable response. Many patients with the best response to immunotherapy develop immunotherapy-induced melanoma-associated vitiligo (MAV), an autoimmune cutaneous side effect. Previous mouse work has revealed that tissue-resident memory T cells (TRM) in vitiligo-skin with specificity for melanoma antigens were required for long-lived protection against melanoma. By examining human specimens, our recent studies revealed that long-term melanoma survivors with MAV maintain tissue-resident memory T cells (TRM) which were long-lived and functional. TRM have recently been recognized by our group and others as critical participants in anti-tumor immune responses. We identified a TRM subset characterized by high interferon gamma expression (TRM-IFNG) that is highly prognostic for improved survival in melanoma patients. Strikingly, TRM-IFNG cells had precursors in the patient’s primary melanoma up to 6 years prior, showing durability of the patient’s natural immune memory response. While there have been many studies focusing on metastatic melanoma, there is a gap of knowledge in understanding how the immune response to primary melanoma affects the recurrence and overall survival of melanoma patients. The goal of this proposal is to investigate the TRM response at the time of primary melanoma diagnosis and test its requirement for immunotherapy response. Our hypothesis is TRM-IFNG cells are established at the time of primary melanoma and are recalled and expanded in order to mediate responses to immunotherapy (IT). We will test this using melanoma mouse models as well as prospectively collected patient specimens to determine how TRM-IFNG formed in skin and tumor at the time of initial melanoma occurrence mediate responses to immunotherapy in the metastatic setting. In a precl