Opposing immune and genetic forces shape oncogenic programs in synovial sarcoma

Jerby, L.; Neftel, C.; Shore, M. E.; McBride, M. J.; Haas, B.; Izar, B.; Weissman, H. R.; Volorio, A.; Boulay, G.; Cironi, L.; Richman, A. R.; Broye, L. C.; Gurski, J. M.; Luo, C. C.; Mylvaganam, R.; Nguyen, L.; Mei, S.; Melms, J. c.; Georgescu, C.; Cohen, O.; Buendia-Buendia, J. E.; Cuoco, M. S.; Labes, D.; Zollinger, D. R.; Beechem, J. M.; Nielsen, P.; Chebib, I.; Cote, G.; Choy, E.; Letovanec, I.; Cherix, S.; Wagle, N.; Sorger, P. K.; Haynes, A. B.; Mullen, J. T.; Stamenkovic, I.; Rivera, M. N.; Kadoch, C.; Rozenblatt-Rosen, O.; Suva, M. L.; Riggi, N.; Regev, A.

doi:10.1101/724302

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bioRxiv · 10.1101/724302

Opposing immune and genetic forces shape oncogenic programs in synovial sarcoma

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Abstract

Synovial 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.

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Jerby, L., Neftel, C., Shore, M. E., McBride, M. J., Haas, B., Izar, B., Weissman, H. R., Volorio, A., Boulay, G., Cironi, L., Richman, A. R., Broye, L. C., Gurski, J. M., Luo, C. C., Mylvaganam, R., Nguyen, L., Mei, S., Melms, J. c., Georgescu, C., Cohen, O., Buendia-Buendia, J. E., Cuoco, M. S., Labes, D., Zollinger, D. R., Beechem, J. M., Nielsen, P., Chebib, I., Cote, G., Choy, E., Letovanec, I., Cherix, S., Wagle, N., Sorger, P. K., Haynes, A. B., Mullen, J. T., Stamenkovic, I., Rivera, M. N., Kadoch, C., Rozenblatt-Rosen, O., Suva, M. L., Riggi, N., Regev, A.. 2019-08-04. Opposing immune and genetic forces shape oncogenic programs in synovial sarcoma. https://doi.org/10.1101/724302

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