Single-Cell Transcriptome & Effect of Immune Checkpoint Therapy on Kaposi Sarcoma

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Abstract – Single-Cell Transcriptome & Effect of Immune Checkpoint Therapy on Kaposi Sarcoma Kaposi Sarcoma (KS) is a malignancy resulting from KS γ-herpresvirus (KSHV) infection occurring in immunosuppressed individuals, as well as a disease occurring primarily in males in subSaharan Africa and southern Mediterranean countries. The tumor is thought to arise from lymphatic endothelial cells, but it is pathologically complex with an admixture of vascular-like slits, spindle cells, and infiltrating inflammatory cells. KSHV is found in a subset of tumor cells with either lytic or latent gene expression profiles. Due to this complexity, there is very limited information about genomic and transcriptomic characteristics of this malignancy. The development of single cell (sc) transcriptomics (RNA-seq) provides a unique opportunity to identify key characteristics that underlie the development of KS. Treatment of KS involves local therapies, chemotherapy, angiogenesis or proteasome inhibitors, or immunotherapies, such as immunomodulatory drugs (IMiDs) or immune checkpoint inhibitors. Recent findings have suggested that KS responds to inhibitors of the programmed death-1(PD-1) pathway in approximately 20- 30% of individuals, but may rarely cause severe inflammatory KSHV-associated disorders. The current project will take advantage of an expansion arm of our current trial of nivolumab in HIV-associated KS. We will select samples before and after 2 months of nivolumab treatment from the 5 individuals with the best response and 5 individuals with progressive disease or no response to treatment. One goal of the current project is to identify pre-treatment characteristics, using scRNA-seq, that predict response or progression of KS treatment with PD- 1 inhibitor, nivolumab. A second goal of this project is to determine what changes of cell composition and gene expression occur with nivolumab in tumor cells and the tumor microenvironment. The aims are as follows: Aim 1. Determine the effect of PD-1 checkpoint inhibitor therapy on lymphoid infiltration into KS tumors. We will use scRNA-seq to enumerate B, CD4+ and CD8+ lymphocytes, natural killer, dendritic, and plasma cells, macrophages, mesenchymal, endothelial, and other cells in samples before and after nivolumab treatment. Aim 2. Determine the effect of PD-1 checkpoint inhibitor therapy on cellular and viral gene expression. We will use scRNA-seq to quantify levels of expression of KSHV lytic and latent genes, as well as expression of cellular genes in angiogenesis, proliferation, apoptosis, and metabolic pathways.