MDSC-mediated immune suppression as a driver of HIV and Melanoma co-morbidity 2919

Abstract Description Although antiretroviral therapies have extended lifespans for people living with HIV (PLWH), the novel population of aging PLWH are now affected by age-related non-AIDs defining cancers, like cutaneous melanoma where PLWH have a 4x greater mortality rate than age-matched controls. The biological mechanisms for this mortality are understudied but may be due to chronic inflammation and an increase in immunosuppressive myeloid-derived suppressor cells (MDSCs) in PLWH. We have completed the first-ever immune-focused spatial transcriptomics analysis of melanoma tumors and microenvironments in PLWH to uncover increases in genes related to an immune suppressed/exhausted tumor environment (i.e. MDSCs, fibrosis, TREGs, and T cell exhaustion). Next, we established two novel models to study these aspects further. First, we built and optimized a novel in vitro culture of melanoma, and HIV+ patient derived CD8+ T cells and MDSCs to study their influence on CD8+ T cell exhaustion. Second, we developed a novel immune-competent murine model of HIV and syngeneic melanoma that displayed significant increases in tumor burden and fibrosis compounded with an altered immune infiltrate. Overall, our models indicate that PLWH with melanoma present with an immune suppressive/exhaustive tumor microenvironment which is mirrored in our immune-competent model of HIV and melanoma co-morbidity and is potentially druggable with MDSC-directed strategies in combination with standard-of-care immunotherapies. Funding Sources Translational Research Training Grant in NeuroHIV - NIMH, T32-MH079785 Comprehensive NeuroHIV Center (CNHC) Developmental Research and Mentoring Core - NIMH - P30MH092177 WW Smith Charitable Trust - Medical Research Program (#C2303) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)