小柯机器人

美国哈佛大学麻省理工学院Aviv Regev以及美国麻萨诸塞州总医院和哈佛医学院Nicolò Riggi、Mario L. Suvà研究组合作取得一项新突破。他们的最新研究提出相反的免疫和遗传机制影响滑膜肉瘤（SyS）的致癌程序。这一研究成果发表在2021年1月25日出版的《自然-医学》杂志上。

他们使用整合了单细胞RNA测序（scRNA-seq）、空间谱分析以及遗传和药理学扰动的综合方法研究了SyS中的肿瘤-免疫相互作用。来自12个人类SyS肿瘤的16,872个细胞的scRNA-seq发现了一个恶性亚群，该亚群标志着原位免疫剥夺环境，并预测了两个独立队列中较差的临床结果。

功能分析表明，这种恶性细胞状态受SS18-SSX融合的控制，被巨噬细胞和T细胞分泌的细胞因子所抑制，并且可以与HDAC和CDK4 / CDK6抑制剂协同靶向。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细胞介导的杀伤作用。

他们的研究为研究融合驱动的恶性肿瘤的异质性提供了一个蓝图，并证明了免疫逃逸和致癌过程之间的相互作用，可以共同针对SyS和潜在的其他恶性肿瘤。

据介绍，SyS是由SS18-SSX融合驱动的侵袭性肿瘤，其特征在于低T细胞浸润。

附：英文原文

Title: Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma

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

Issue&Volume: 2021-01-25

Abstract: 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.

DOI: 10.1038/s41591-020-01212-6

Source: https://www.nature.com/articles/s41591-020-01212-6

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex