Tissue-resident memory T cells are diminished in the Kaposi sarcoma tumor microenvironment of people living with HIV

Kaposi sarcoma (KS) is a rare neoplasm and an AIDS-defining diagnosis in people living with HIV (PLWH). Although and chronic infection with Kaposi sarcoma-associated herpesvirus (KSHV) contributes to KS progression, the local immune mechanisms that are lost during tumor progression remain incompletely understood. Here, we systematically characterized global patterns in the KS tumor microenvironment (TME) in both PLWH and HIV-negative individuals. Spatial transcriptomics revealed distinct niches comprising of tumor cells, immune cells, and surrounding skin cells. Tumor regions expressed a characteristic endothelial-fibroblastic signature attributable to KS tumor cells (CD34, LYVE1, SCN9A), TME regions expressed marker genes for T cells, B cells and cancer-associated fibroblasts. Analysis of putative cell-cell interactions demonstrated that tumor cells preferentially interact with cells of the TME, including T cells, indicating an important role as hub of cellular communication in KS. Immunofluorescence imaging confirmed increased numbers of T cells, specifically tissue-resident memory T cells (TRM), in KS samples compared to healthy skin, accompanied by a pronounced upregulation of PD-1 expression that was predominantly localized to the TME. Notably, we identified HIV-associated alterations in the KS immune microenvironment: PLWH exhibited loss of CXCR3+ and IFN-gamma producing CD8+ TRM cells in the KS TME compared to HIV-negative patients, a finding consistent with impaired antitumor immunity. Together, our findings reveal HIV-associated disruption of functional anti-tumor immunity in the KS TME of PLWH. Increased PD-1 expression within T cells of the TME highlights potential therapeutic use of immune checkpoint inhibitors in KS.