Population analysis and immunologic landscape of melanoma in people living with HIV

To dissect the clinical and immunological features of people living with HIV (PLWH) diagnosed with melanoma, who have consistently exhibited worse clinical outcomes than HIV-negative individuals (PLw/oH) with the same cancer.

We analyzed electronic health records from 1,019 PLWH and 373,121 PLw/oH diagnosed with melanoma. Demographic and clinical characteristics were compared. Spatial immune transcriptomics (72 immune-related genes) was performed on melanoma tumor samples (n=11), followed by downstream validation using multiplex immunofluorescence (n=15 PLWH, n=14 PLw/oH).

PLWH were diagnosed with melanoma at a younger age, had a higher representation of Hispanic and Black individuals compared to PLw/oH, and a decreased survival rate. PLWH also showed a markedly increased risk of brain metastases. PLWH experienced significant delays in initiating immune checkpoint inhibitor (ICI) therapy and had worse survival outcomes following ICI, even after balancing for demographic covariates. Spatial transcriptomics revealed a more immunosuppressive tumor microenvironment in PLWH, with upregulation of immune checkpoints (PD1, LAG3) and reduced expression of antigen presentation markers (HLA-DRB, B2M), with distinct spatial distributions in tumors and their microenvironments. Multiplex immunofluorescence confirmed an exhausted CD8⁺ T cell compartment in PLWH, including enrichment of PD1^intLAG3^- and PD1^intLAG3⁺ subpopulations, and a significant accumulation of immunosuppressive myeloid-derived suppressor cells (CD11b⁺ HLA-DR^- CD33⁺).

Our findings suggest chronic HIV infection fosters a permissive tumor microenvironment that might undermine effective immune responses and contribute to poor clinical outcomes for PLWH with melanoma. Targeting the actionable immune pathways identified in this study could inform tailored therapeutic strategies to mitigate these disparities.