Abstract
PURPOSE: To dissect the clinical and immunologic features of people living with human immunodeficiency virus (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 (mIF; n = 15 PLWH, n = 14 PLw/oH). RESULTS: PLWH were diagnosed at a younger age, had a 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 (PD-1, LAG3) and reduced antigen-presentation markers (HLA-DRB, B2M), along with distinct spatial distributions in tumors and surrounding microenvironments. mIF demonstrated features of an exhausted CD8+ T-cell compartment, including enrichment of PD-1intLAG3- and PD-1intLAG3+ subpopulations and a significant accumulation of myeloid-derived suppressor cells (MDSC; CD11b+ HLA-DR- CD33+). CONCLUSIONS: Melanoma in PLWH is associated with distinct clinical and immunologic features, including delayed ICI treatment, reduced survival, and an immunosuppressive microenvironment with exhausted CD8+ T cells and expanded MDSCs. 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.