Immunologic Landscape and Outcomes of Melanoma in HIV-Positive Individuals

Purpose: To dissect the clinical and immunological features of people living with HIV (PLWH) diagnosed with melanoma, who have consistently shown worse outcomes than HIV-negative individuals (PLw/oH) with the same cancer. Experimental Design: We analyzed electronic health records from 1,087 PLWH and 394,437 PLw/oH with melanoma. Demographic and clinical characteristics were compared. Spatial immune transcriptomics (72 immune-related genes) was performed on melanoma tumor samples (n=11), with downstream validation using multiplex immunofluorescence (n=15 PLWH, n=14 PLw/oH). Results: PLWH were diagnosed at a younger age, had greater representation of Hispanic and Black individuals, and showed reduced survival. They also had a markedly increased risk of brain metastases. PLWH experienced significant delays in initiating immune checkpoint inhibitor (ICI) therapy and had worse post-ICI survival, even after balancing covariates. Spatial transcriptomics revealed a more immunosuppressive tumor microenvironment in PLWH, with increased transcription of immune checkpoints (PD1, LAG3) and reduced antigen-presentation markers (HLA-DRB, B2M), with distinct spatial distributions in tumors and surrounding microenvironments. Multiplex immunofluorescence demonstrated features of an exhausted CD8+ T cell compartment, including enrichment of PD1intLAG3- and PD1intLAG3+ subpopulations, and a significant accumulation of myeloid-derived suppressor cells (CD11b+ HLA-DR- CD33+). Conclusions: Melanoma in PLWH is associated with distinct clinical and immunological features, including delayed ICI treatment, reduced survival, and an immunosuppressive microenvironment with exhausted CD8+ T cells and expanded myeloid-derived suppressor cells. These findings suggest that chronic HIV infection may impair antitumor immunity in melanoma. Targeting the pathways identified here may improve therapeutic responses and outcomes in this population. Citation Format: Lindsay Barger, Derek Wang, Ashley Saravia, Valeria Mezzano-Robinson, Gyles Ward, Cynthia Loomis, Carly Feldman, Madalina Tuluc, Rino S. Seedor, Peter J. Gaskill, Anna E. Coghill, Gita Suneja, Iman Dehzangi, Jenna Hope, George Jour, Gabriele Romano. Population analysis and immunologic landscape of melanoma in people living with HIV [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7862.