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

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.