Abstract C021: Characterization of a Novel Inducible Mouse Model of Synovial Sarcoma

Abstract

For children and young adults with recurrent and refractory synovial sarcoma, outcomes remain poor with a distinct need for improved therapeutic approaches. While immune checkpoint inhibition demonstrated limited efficacy in synovial sarcoma, recent advancement of T-cell receptor therapy targeting cancer testis antigens has renewed interest in immunotherapy approaches for synovial sarcoma. Accordingly, immunocompetent mouse models of synovial sarcoma are critical for ongoing immunotherapy development and assessment of combinatorial therapy approaches. We developed a robust, inducible mouse model of synovial sarcoma driven by the SS18-SSX2 fusion protein in which intramuscular injection of Cre protein induced expression of the fusion protein, deletion of Pten, and activation of β-catenin. Tumors were established within three weeks of injection with 100% penetrance and histologic features consistent with synovial sarcoma. Bulk RNA sequencing confirmed WNT and P13K pathway activation. The tumor was further characterized with single-cell RNA sequencing and Xenium spatial characterization, capturing distinct niches within the tumor immune microenvironment. Gene set enrichment analysis demonstrated unique features compared to other established synovial sarcoma mouse modeling, including MYC target and epithelial mesenchymal transition associated genes. Cell lines established from the tumor demonstrated varying sensitivity to doxorubicin, vincristine, SN38 (active metabolite of irinotecan), and pazopanib. Collectively, our model provides rapid establishment of tumors histologically consistent with synovial sarcoma. Characterization demonstrates a robust tumor immune microenvironment with chemotherapy sensitivity and distinct genomic profiling. This model provides a unique opportunity for characterizing synovial sarcoma biology, dissecting the tumor immune microenvironment, and exploring combinatorial immunotherapy approaches in the effort to improve therapeutic options for individuals with synovial sarcoma.