Abstract
Abstract
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 (T
RM
), 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-γ–producing CD8⁺ T
RM
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.
What is already known on this topic
While systemic immunosuppression and viral replication are known drivers of KS progression, the local, microanatomical immune mechanisms governing tumor control remain under-investigated. Specifically, how HIV infection functionally alters antitumor immunity within the local tumor TME and why PLWH frequently exhibit impaired antitumor responses compared to HIV-negative individuals, has not been investigated.
What this study adds
This study provides a spatially resolved cellular and transcriptomic map of the KS microenvironment across both PLWH and HIV-negative cohorts, indicating that T cells in the KS TME serve as a primary hub of cellular communication. Crucially, we discovered an HIV-specific loss of functional, CXCR3+CD8+ T
RM
cells in the TME. Lastly, we identify activity of co-inhibitory receptor pathways and high PD-1 expression in KS-associated T cells.
How this study might affect research, practice or policy
These findings advance tumor immunology by defining functional impairment and local depletion of T
RM
as a hallmark of HIV-associated malignancy. Furthermore, the pronounced upregulation of PD-1 within the TME provides a strong biological rationale for the use of immune checkpoint inhibitors in patients with KS.
Graphical Abstract
KS lesions are populated by cytokine-producing CXCR3+ PD-1+ T cells. TME in HIV-associated KS is characterized by loss of IFN-g-producing T
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leading to impaired functional tumor-immunity. (Created in BioRender. Strobl, J. (2026)
https://BioRender.com/drwi6gk
.)