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

People living with HIV (PLWH) diagnosed with melanoma have consistently exhibited worse clinical outcomes than HIV-negative individuals (PLw/oH) with the same cancer, even in the era of antiretroviral therapy (ART). To investigate the underlying factors contributing to these disparities, we analyzed electronic health records from 922 PLWH and 334,972 PLw/oH with melanoma. PLWH were diagnosed with melanoma at a younger age and had a higher representation of Hispanic and Black individuals. Notably, PLWH had a markedly increased risk of brain metastases. Additionally, despite similar treatment durations, PLWH experienced significant delays in initiating immune checkpoint therapy (ICI) and exhibited worse survival outcomes at both five- and ten-years post-treatment with ICI.

To explore potential biological determinants of these disparities, we conducted spatial immune transcriptomics on melanoma tumors (n=11). This analysis revealed a more immunosuppressive tumor landscape in PLWH, characterized by upregulated immune checkpoints (e.g.,PD1, LAG3, CTLA4)and diminished antigen presentation (e.g.,HLA-DRB, B2M), with distinct spatial distributions in the tumors versus the tumor microenvironments. Downstream validation via multiplex immunofluorescence (n=15 PLWH, n=14 PLw/oH) confirmed an exhausted CD8⁺T cell compartment, marked by enrichment of PD1^intLAG3⁻and PD1^intLAG3⁺subpopulations, along with a significant accumulation of immunosuppressive myeloid-derived suppressor cells (CD11b⁺HLA-DR⁻CD33⁺) in PLWH.

These distinct immune profiles 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.