Role of Vgll3-driven Type I IFN in Shaping the Sarcoma Immune Landscape 9365

Abstract Description Tumor-immune infiltration is an important predictor of immunotherapy response in undifferentiated pleomorphic sarcoma (UPS). However, most patients respond poorly to immunotherapy due to a lack of tumor infiltrating T cells and an enrichment of tumor-promoting macrophages. Increasing tumor-immune infiltration is therefore critical to improve survival and treatment response in UPS patients. Our goal is to determine why some tumors recruit more immune cells than others. We are investigating how Vgll3, a frequently overexpressed gene in UPS, regulates tumor immune infiltration. In a mouse model of UPS, recent work showed increased immune infiltration into Vgll3-overexpressing tumors (Vgll3+) and a robust response to chemotherapy compared to immune-excluded sarcomas. We are now defining the cellular and molecular mechanisms by which Vgll3 drives immune infiltration to identify pathways that could potentially be targeted therapeutically in genetically distinct, immune-excluded tumors. We observed stronger type I IFN production by Vgll3+ sarcoma cells than sarcoma cells with normal levels of Vgll3, and that Vgll3+ tumors are enriched in a subset of immunostimulatory IFN-responsive classical monocytes. Our studies will reveal new insights into the mechanisms of sarcoma-immune cell infiltration, highlight differential responses of immune subsets to tumor-derived factors, and uncover therapeutic targets to enhance treatment response and survival outcome in UPS patients. Funding Sources Supported by funds from the Board of Governors Regenerative Medicine Institute at Cedars-Sinai (to HSG). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)