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Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma
Nature Medicine ( IF 82.9 ) Pub Date : 2021-01-25 , DOI: 10.1038/s41591-020-01212-6
Livnat Jerby-Arnon 1, 2, 3, 4 , Cyril Neftel 3, 4, 5, 6 , Marni E Shore 3, 4, 5 , Hannah R Weisman 3, 4, 5 , Nathan D Mathewson 7, 8, 9 , Matthew J McBride 10 , Brian Haas 3, 4 , Benjamin Izar 3, 11, 12 , Angela Volorio 3, 5 , Gaylor Boulay 3, 5 , Luisa Cironi 6 , Alyssa R Richman 3, 4, 5 , Liliane C Broye 6 , Joseph M Gurski 13 , Christina C Luo 5 , Ravindra Mylvaganam 5 , Lan Nguyen 3 , Shaolin Mei 14 , Johannes C Melms 11, 12 , Christophe Georgescu 3 , Ofir Cohen 3, 4, 15 , Jorge E Buendia-Buendia 15 , Asa Segerstolpe 3 , Malika Sud 3 , Michael S Cuoco 3, 16 , Danny Labes 17 , Simon Gritsch 3, 4, 5 , Daniel R Zollinger 18 , Nicole Ortogero 18 , Joseph M Beechem 18 , G Petur Nielsen 5 , Ivan Chebib 13 , Tu Nguyen-Ngoc 19 , Michael Montemurro 19 , Gregory M Cote 20 , Edwin Choy 20 , Igor Letovanec 6 , Stéphane Cherix 21 , Nikhil Wagle 3, 15 , Peter K Sorger 14 , Alex B Haynes 22 , John T Mullen 22 , Ivan Stamenkovic 6 , Miguel N Rivera 3, 5 , Cigall Kadoch 3, 10 , Kai W Wucherpfennig 3, 7, 8 , Orit Rozenblatt-Rosen 3, 4, 23 , Mario L Suvà 3, 4, 5 , Nicolò Riggi 5, 6 , Aviv Regev 3, 4, 23, 24
Affiliation  

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.



中文翻译:

对立的免疫和遗传机制塑造了滑膜肉瘤的致癌程序

滑膜肉瘤 (SyS) 是一种由 SS18-SSX 融合驱动的侵袭性肿瘤,以低 T 细胞浸润为特征。在这里,我们使用结合单细胞 RNA 测序 (scRNA-seq)、空间分析以及遗传和药理学扰动的综合方法研究了 SyS 中的癌症-免疫相互作用。来自 12 个人类 SyS 肿瘤的 16,872 个细胞的 scRNA-seq 揭示了一个恶性亚群,该亚群在原位标记了免疫剥夺的生态位,并预测了两个独立队列中不良的临床结果。功能分析表明,这种恶性细胞状态受 SS18-SSX 融合控制,被巨噬细胞和 T 细胞分泌的细胞因子抑制,并且可以与 HDAC 和 CDK4/CDK6 抑制剂的组合协同靶向。这种药物组合增强了 SyS 模型中的恶性细胞免疫原性,导致诱导的 T 细胞反应性和 T 细胞介导的杀伤。我们的研究为研究融合驱动的恶性肿瘤的异质性提供了蓝图,并证明了免疫逃避和致癌过程之间的相互作用,这些过程可以共同靶向 SyS 和其他恶性肿瘤。

更新日期:2021-01-25
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