Feldman, C. | Search bioRxiv

bioRxiv2025

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

PurposeTo 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 DesignWe 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). ResultsPLWH 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). ConclusionsMelanoma 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. Statement of translational relevanceThis study reveals critical barriers to effective melanoma treatment in people living with HIV (PLWH). Despite receiving immune checkpoint inhibitors (ICIs), PLWH face delayed therapy initiation, a greater likelihood of brain metastases, and significantly higher long-term mortality, even after adjusting for demographic covariates. Transcriptional immune profiling further uncovers a tumor microenvironment enriched in immunosuppressive myeloid-derived suppressor cells and CD8 T cell populations with features of exhaustion. These findings suggest that poorer outcomes in PLWH stem not only from delayed care, but also from distinct targetable mechanisms of immune dysfunction. For example, strategies to reverse MDSC accumulation in the tumor or tailored ICI regimens could enhance immune responsiveness and improve treatment efficiency. By defining the clinical and immunological features of this population, this work highlights opportunities for precision immunotherapy tailored to PLWH with melanoma, with direct implications for improving survival and reducing disparities.

cancer biology↗

bioRxiv2019

Genetic structure of prey populations underlies the geographic mosaic of arms race coevolution

Reciprocal adaptation is the hallmark of arms race coevolution, but the symmetry of evolutionary change between interacting species is often untested, even in the best-studied battles of natural enemies. We tested whether prey and predator exhibit symmetrical local co-adaptation in the example of a geographic mosaic of coevolution between toxic newts (Taricha granulosa) and resistant garter snakes (Thamnophis sirtalis). Prior work showing a tight correlation between levels of newt toxin and snake resistance is regarded as textbook evidence of the intense arms race between natural enemies. Here, we similarly found that toxin and resistance are functionally matched in prey and predator populations, further suggesting that mosaic variation in the armaments of both species results from the local pressures of reciprocal selection. Contrary to conventional wisdom, however, we found that local variation in newt toxin is best predicted by neutral population divergence rather than the resistance of co-occurring predators. Snake resistance, on the other hand, is clearly explained by local levels of prey toxin. Prey populations seem to structure variation in defensive toxin levels across the geographic mosaic, which in turn determines selection on predator resistance. Exaggerated armaments suggest that coevolution occurs in certain hotspots, but our results imply that neutral processes like gene flow--rather than reciprocal adaptation--structure the greatest source of variation across the landscape. This pattern supports the predicted role of \"trait remixing\" in the geographic mosaic of coevolution, the process by which non-adaptive forces dictate spatial variation in the interactions among species.\n\nSIGNIFICANCE STATEMENTWhen the weapons of natural enemies like prey toxins and predator resistance are matched across the geographic landscape, they are usually presumed to result from arms race coevolution. In the textbook example of an arms race, matched levels of newt toxin and garter snake resistance have long been regarded as evidence of such local co-adaptation. To the contrary, we found that local variation in newt toxicity is best explained by the neutral geographic structure of newt populations. This spatial variation of prey in turn dictates local selection on garter snakes, structuring the geographic pattern of predator resistance. These results demonstrate how landscape patterns of phenotypic variation are determined by a mixture of natural selection, historical biogeography, and gene flow that comprise the geographic mosaic of coevolution.

evolutionary biology↗