Dissecting the tumor-immune landscape of melanoma in people living with HIV: insights into myeloid-T cell crosstalk and immune suppression

Lindsay Nicole Barger

doi:10.17918/00011334

The widespread adoption of antiretroviral therapy (ART) has transformed HIV-1 infection into a chronic, manageable condition, dramatically improving life expectancy for people living with HIV (PLWH). However, as survival has increased, non-AIDS-defining cancers have emerged as a growing cause of mortality in this population. Cutaneous melanoma represents a particularly concerning malignancy: although PLWH exhibit only modestly increased incidence compared to people living without HIV (PLw/oH), melanoma-specific mortality is approximately fourfold higher, even after adjusting for stage at diagnosis, treatment access, and ART use. These persistent disparities suggest that viral suppression alone does not normalize cancer outcomes and instead implicate chronic HIV-associated immune dysfunction as a driver of impaired anti-tumor immunity. The biological mechanisms underlying this vulnerability remain poorly understood. To address this critical gap, we integrated clinical, high-dimensional genetic, and functional analyses to define how chronic HIV-1 infection shapes melanoma progression and immune responses. First, we interrogated publicly available melanoma datasets to compare demographics, metastatic risk, and survival outcomes between PLWH and PLw/oH, confirming significant disparities in melanoma-specific survival. We then performed the first immune-focused spatial transcriptomic analysis of melanoma tumors stratified by HIV-1 status, enabling high-resolution characterization of tumor-associated immune populations. These findings were validated using multiplex immunofluorescence to define immune phenotypes and subpopulations within the tumor microenvironment. Our tumor analyses revealed a profoundly altered immune landscape in PLWH, characterized by increased T cell exhaustion and expansion of immature myeloid populations phenotypically resembling myeloid-derived suppressor cells (MDSCs). Notably, in an independent cohort of PLWH without melanoma, we also identified elevated circulating immature myeloid populations resembling monocytic MDSCs at baseline, demonstrating that this phenotype is shared across PLWH with and without melanoma. To mechanistically dissect how these alterations influence anti-tumor immunity, we developed a novel in vitro triple-culture system modeling interactions among CD8+ T cells, melanoma cells, and MDSCs. This platform enabled direct quantification of MDSC-mediated immunosuppression and comparison of intrinsic CD8+ T cell cytotoxic capacity between PLWH and PLw/oH. Functional assays, although limited in statistical power at this time, indicated that exposure to MDSCs from PLWH resulted in modestly increased expression of exhaustion markers LAG3, PD-1, as well as reduced granzyme B release. This suggested the potential for impaired cytotoxicity against melanoma cells or an increased rate of cell exhaustion. Collectively, these findings demonstrate that PLWH, compared to HIV-negative controls, harbor elevated suppressive myeloid populations, and that in the context of melanoma, this is associated with diminished anti-tumor immunity, highlighting opportunities for targeted therapeutic intervention.

Dissecting the tumor-immune landscape of melanoma in people living with HIV: insights into myeloid-T cell crosstalk and immune suppression

Files and links (1)

Abstract

Metrics

Details

Dissecting the tumor-immune landscape of melanoma in people living with HIV: insights into myeloid-T cell crosstalk and immune suppression

Files and links (1)

Abstract

Metrics

Details

Drexel University Social media