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Haas, Brian

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Haas, Brian

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    Opposing Immune and Genetic Mechanisms Shape Oncogenic Programs in Synovial Sarcoma
    (Cold Spring Harbor Laboratory, 2021-01-25) Jerby-Arnon, Livnat; Neftel, Cyril; Shore, Marni E.; Weisman, Hannah R.; Mathewson, Nathan; McBride, Matthew J.; Haas, Brian; Izar, Benjamin; Volorio, Angela; Boulay, Gaylor; Cironi, Luisa; Richman, Alyssa R.; Broye, Liliane C.; Gurski, Joseph M.; Luo, Christina; Mylvaganam, Ravindra; Nguyen, Lan; Mei, Shaolin; Melms, Johannes; Georgescu, Christophe; Cohen, Ofir; Buendia Buendia, Jorge Eduardo; Segerstolpe, Asa; Sud, Malika; Cuoco, Michael; Labes, Danny; Zollinger, Daniel R.; Ortogero, Nicole; Beechem, Joseph M.; Nielsen, G. Petur; Chebib, Ivan; Nguyen-Ngoc, Tu; Montemurro, Michael; Cote, Gregory; Choy, Edwin; Letovanec, Igor; Cherix, Stéphane; Wagle, Nikhil; Sorger, Peter; Haynes, Alex; Mullen, John; Stamenkovic, Ivan; Rivera, Miguel; Kadoch, Cigall; Wucherpfennig, Kai; Rozenblatt-Rosen, Orit; Suvà, Mario L.; Riggi, Nicolò; Regev, Aviv
    ABSTRACTSynovial sarcoma is an aggressive mesenchymal neoplasm, driven by the SS18-SSX fusion, and characterized by immunogenic antigens expression and exceptionally low T cell infiltration levels. To study the cancer-immune interplay in this disease, we profiled 16,872 cells from 12 human synovial sarcoma tumors using single-cell RNA-sequencing (scRNA-Seq). Synovial sarcoma manifests antitumor immunity, high cellular plasticity and a core oncogenic program, which is predictive of low immune levels and poor clinical outcomes. Using genetic and pharmacological perturbations, we demonstrate that the program is controlled by the SS18-SSX driver and repressed by cytokines secreted by macrophages and T cells in the tumor microenvironment. Network modeling predicted that SS18-SSX promotes the program through HDAC1 and CDK6. Indeed, the combination of HDAC and CDK4/6 inhibitors represses the program, induces immunogenic cell states, and selectively targets synovial sarcoma cells. Our study demonstrates that immune evasion, cellular plasticity, and cell cycle are co-regulated and can be co-targeted in synovial sarcoma and potentially in other malignancies.