1982P Transcriptomic analysis and tumor microenvironment (TME) classification reveals unique immune biology in HIV patients with Kaposi sarcoma (KS)

KS, associated with human herpesvirus 8 (KSHV) infection, is a tumor originating from endothelial cells. As a common tumor associated with AIDS, KS is typically more aggressive in HIV-positive (HIV+) than in HIV-negative (HIV-) patients (pts). While antiretroviral therapy helps control KS in HIV+ pts, chemotherapy remains the first-line treatment (Tx) in advanced KS but is limited by modest responses and dose-limiting toxicities. The TME has been shown to play a critical role in KS development and progression. Here, we sought to understand the TME in KS, with a specific focus on the differences in HIV status. Whole transcriptomic profiling was performed on 13 retrospective samples from 9 pts (HIV+: n = 6, HIV- n =3; mostly baseline, except 2 HIV- and 2 HIV+ pts had paired samples before and after Tx). A deconvolution algorithm Kassandra was used to predict cellular composition with pre-training on sarcoma samples, and EdgeR was used for differential expression analysis. TME subtypes were classified based on a previous study (Bagaev et al., 2021) assessing sarcoma-related gene expression patterns. All KS samples were enriched with endothelial cells and had characteristics of a typical sarcoma TME with an abundance of macrophages and normal amounts of B cells. Most HIV- pts had an Immune-Enriched, Non-fibrotic subtype, while HIV+ pts had immune-Enriched, Fibrotic or Fibrotic TMEs. Decreased angiogenic signatures were observed after Tx in HIV+ pts with paired samples. Expression levels of chemokines (CXCL2, CXCL8, CXCL11), chemokine receptors (CCR1-7, CXCR1-2), and CCL factors were higher in pre-Tx HIV- pts versus post-Tx and post-TX HIV+ pts versus pre-TX. PD-L1 and PD-L2 expressions were higher in HIV- pts before Tx and in HIV+ pts after Tx. In 3 HIV- and 2 HIV+ pts, for whom TCR. Our results showed distinct transcriptomic features and TMEs between HIV+ and HIV- KS in responses to Tx. Future larger cohorts and research into the unique T cell clonotypes may help yield novel therapeutic avenues in KS.