Details

Autor(en) / Beteiligte

• Jerby-Arnon, Livnat
• Neftel, Cyril
• Shore, Marni E
• Weisman, Hannah R
• Mathewson, Nathan D
• McBride, Matthew J
• Haas, Brian
• Izar, Benjamin
• Volorio, Angela
• Boulay, Gaylor
• Cironi, Luisa
• Richman, Alyssa R
• Broye, Liliane C
• Gurski, Joseph M
• Luo, Christina C
• Mylvaganam, Ravindra
• Nguyen, Lan
• Mei, Shaolin
• Melms, Johannes C
• Georgescu, Christophe
• Cohen, Ofir
• Buendia-Buendia, Jorge E
• Segerstolpe, Asa
• Sud, Malika
• Cuoco, Michael S
• Labes, Danny
• Gritsch, Simon
• Zollinger, Daniel R
• Ortogero, Nicole
• Beechem, Joseph M
• Petur Nielsen, G
• Chebib, Ivan
• Nguyen-Ngoc, Tu
• Montemurro, Michael
• Cote, Gregory M
• Choy, Edwin
• Letovanec, Igor
• Cherix, Stéphane
• Wagle, Nikhil
• Sorger, Peter K
• Haynes, Alex B
• Mullen, John T
• Stamenkovic, Ivan
• Rivera, Miguel N
• Kadoch, Cigall
• Wucherpfennig, Kai W
• Rozenblatt-Rosen, Orit
• Suvà, Mario L
• Riggi, Nicolò
• Regev, Aviv

Titel

Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma

Ist Teil von

• Nature medicine, 2021-02, Vol.27 (2), p.289-300

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. Here, we studied the cancer-immune interplay in SyS using an integrative approach that combines single-cell RNA sequencing (scRNA-seq), spatial profiling and genetic and pharmacological perturbations. scRNA-seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune-deprived niches in situ and is predictive of poor clinical outcomes in two independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. This drug combination enhanced malignant-cell immunogenicity in SyS models, leading to induced T cell reactivity and T cell-mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.