In-depth characterisation of the tumour microenvironment reveals HHV-8-dependent immune regulation in HIV-associated and classic Kaposi sarcoma

Abstract

BACKGROUND: Kaposi's sarcoma (KS) is the most common malignancy occurring in people living with HIV (PLWH). The clinical course of KS in PLWH established on combined anti-retroviral therapy (cART) resembles that of classic KS. OBJECTIVES: To compare the clinical and biological characteristics of HIV-associated KS in patients with well-controlled viral infection (N = 21) and non-HIV-associated KS (N = 19). METHODS: Clinical data were prospectively collected from patients treated at the National Centre for HIV malignancies at Chelsea & Westminster Hospital. Targeted transcriptomic analysis and multiplex immune-fluorescence were performed on archival tumour samples. RESULTS: Clinical outcomes were comparable between groups. The tumour microenvironment (TME) of non-HIV-associated KS was characterised by transcriptional upregulation of pathways associated with adaptive and innate immunity and angiogenesis. The TME of HIV-associated cases was associated with lower infiltration of activated CD4 cells. In both cohorts, we found the expression of HHV-8 genes to positively correlate with activated CD4, CD8, NK and immune checkpoint gene expression. CONCLUSIONS: The KS TME in the presence of well-controlled HIV infection is characterised by a lower degree of inflammation and more pronounced epithelial to mesenchymal transition. We also identified intra-tumoral HHV-8 gene expression as a driver of TME composition.