Identifying EWS:WT1 Control and The Utility of Neogenes in Desmoplastic Small Round Cell Tumors

Desmoplastic small round cell tumors (DSRCTs) are rare, often incurable abdominal sarcomas that present in pediatric and young adolescent populations. It arises from a translocation resulting in a fusion protein (FP), the primary oncogenic driver DSRCT. However, no current molecular targets against the FP exist, and less than 20% of patients survive beyond five years. Immunotherapy has transformed the treatment of many solid cancers, especially those with high tumor mutational burden – a predictor of response to immune checkpoint inhibitors. However, sarcomas are generally not great candidates for immunotherapies, except for perhaps alveolar soft part sarcoma, undifferentiated pleomorphic sarcoma (UPS), and dedifferentiated liposarcoma (DDLS). Many sarcomas, such as DSRCT, have a single gene translocation and low tumor mutational burden – predicting low response for immune checkpoint inhibitors. Data from our group has rekindled the possibility of exploring immunotherapy in DSRCT. We saw that the FP acts as a transcription factor driving the expression of a set of “neogenes”. Neogenes are usually silent in the genome but can be turned on by the FP – suggesting that the neogenes are DSRCT-specific and may be targeted by immunotherapy. Although the bulk RNA-seq analysis of the MDACC DSRCT specimens suggested that DSRCT may be immunologically cold, recent analysis using single-cell RNA-sequencing and spatial proteomics have revealed distinct immune cell populations with antigen-presenting cells and T-cells within the tumor microenvironment (TME). This suggests that if DSRCT-specific neopeptides are presented on the cell surface by MHC molecules, this could overcome the limitations of immunotherapy for fusion-driven sarcomas with low tumor mutational burdens. We will explore the utility of the neogenes in treating DSRCT. First, we will determine if neogenes are translated into neopeptides and if the neopeptides are bound to MHC. This means that the neopeptides are presented to immune cells. Second, we will assess why there is low tumor infiltration by cataloging the different types of immune cells in the tumor microenvironment. This could provide potential hints to how we may manipulate the immune cells to respond to the neopeptides.