(P 240) NEW INSIGHTS FROM SPATIOTEMPORALLY DEFINED TUMOR INDUCTIONS IN A NOVEL MOUSE MODEL OF SYNOVIAL SARCOMA

Objective: Synovial sarcomas (SS) are driven by the SS18::SSX fusion oncogene, generated by the pathognomonic t(X; 18) translocation. In genetically engineered Rosa26-LSL-SS18-SSX2 mice, conditional activation of the fusion oncogene leads to SS tumor formation in anatomic locations dictated by the spatial expression of Cre recombinase. However, limited control over the timing and site of Cre delivery in these models hampers detailed investigations of tumor evolution and therapeutic responses. Thus, we set out to generate a genetically engineered mouse model of SS that allows precise spatial and temporal control over tumor initiation.

Methods: We developed a novel SS mouse model where Cre protein is locally delivered via intramuscular injection to simultaneously induce SS18::SSX expression, Pten deletion, and β-catenin activation. This strategy generates tumors at the injection site within three weeks with 100% penetrance. The resulting tumors—and cell lines derived from them—exhibit aggressive growth and faithfully recapitulate the histological and molecular features of human SS.

Results: Single-cell RNA sequencing, spatial transcriptomics, and comprehensive immune profiling of these tumors uncovered an unexpected role for B cells in SS pathogenesis. Mechanistic studies indicate that tumor-derived CXCL12 recruits B cells with immunosuppressive properties, which may suppress T cell activity within the tumor microenvironment (TME). While SS is typically ‘immunologically cold’ with limited lymphocyte infiltration, the recent FDA approval of engineered T cells for SS immunotherapy underscores the importance of understanding the mechanisms that regulate T cell function in this context.

Conclusion: Our novel mouse model provides a robust platform for dissecting SS tumor biology and testing new therapeutic approaches. The model also reveals new insights into the immune microenvironment of SS that can lead to new opportunities for immunotherapeutic intervention.