Abstract: The present invention provides novel compositions and methods based on the discovery of the mechanisms and gene expression programs associated with synovial sarcoma. In particular, core oncogenic programs were expressed by a distinct subpopulation of malignant cells and associated with poor clinical outcome, a cell cycle program distinguished cycling from non-cycling cells, with cycling cells having a tendency to be poorly differentiated and indicative of increased risk of metastatic disease, and a (de)differentiation program that can identify poorly differentiated cells, the absence of which was prognostic of metastasis free survival. Methods of treatment include use of HDAC and CDK4/6 inhibitors to block oncogenic program to selectively target synovial sarcoma cells. Finally, macrophages and T cells can mimic the effect of SS18-SSX inhibition by secreting TNFa and IFNg, which allows for adoptive cell therapy to provide cells with increased expression of TNFa and IFNg.

Abstract: The present invention provides novel pan-cancer T cell exhaustion regulators. CXCR6 expressed in CD8+ T cells was specifically identified as regulating anti-tumor immunity. Modulating CXCR6-CXCL16 interaction is useful in modulating anti-tumor immunity. The identified genes may be modulated in T cells for use in adoptive cell transfer. The identified genes may be modulated in vivo.

Abstract: Systems and methods for identifying synthetic lethal (SL) and synthetic dosage lethal (SDL) interactions and networks are provided. Further provided are methods for predicting cancer gene essentiality, drug efficacy and survival of cancer patients using data-driven identification of synthetic lethality in cancer are provided. Novel drug candidates and drug combinations for use in cancer therapy and method for prioritizing existing cancer therapies are also provided.

Abstract: Systems and methods for identifying clinically relevant Synthetic Lethal interactions SLi by analyzing large and diverse cohorts of clinically relevant cancer data, utilizing a data driven approach, termed SLICK, are provided. Further provided are system and methods of utilizing SLICK to uncover therapeutic possibilities in cancer.