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基因组水平筛选揭示影响肿瘤细胞对自然杀伤细胞反应的因素
作者:小柯机器人 发布时间:2021/7/18 13:26:27

美国丹娜-法伯癌症研究所 Constantine S. Mitsiades、Michal Sheffer小组取得一项新突破。他们的最新研究利用基因组水平的筛选确定了影响肿瘤细胞对自然杀伤细胞(NK)反应的因素。这一研究成果于2021年7月12日发表在国际学术期刊《自然-遗传学》上。

为了系统地确定人肿瘤细胞的分子特征,以及它们对人类同种异体自然杀伤 细胞的敏感程度,研究人员量化了数百个由“DNA 条形码”进行分子标注的多种实体瘤细胞系对NK细胞的反应性,并在几种实体瘤细胞系中利用CRISPR基因编辑方法进行了基因组规模的筛选,以功能性探究肿瘤细胞中的哪些基因调节其对NK细胞的反应。这些正交研究显示对NK细胞敏感的肿瘤细胞具有“间充质样”转录特征、染色质重塑复合物的高转录、高表达B7-H6 (NCR3LG1)和低表达HLA-E/抗原呈递基因。

更重要的是,对NK细胞敏感的肿瘤细胞其转录特征与临床样本中对免疫检查点抑制剂 (ICI)的抗性相关。这项研究揭示了影响肿瘤细胞对NK细胞反应的因素,对未来研发基于NK细胞的免疫疗法具有指导意义。

附:英文原文

Title: Genome-scale screens identify factors regulating tumor cell responses to natural killer cells

Author: Michal Sheffer, Emily Lowry, Nicky Beelen, Minasri Borah, Suha Naffar-Abu Amara, Chris C. Mader, Jennifer A. Roth, Aviad Tsherniak, Samuel S. Freeman, Olga Dashevsky, Sara Gandolfi, Samantha Bender, Jordan G. Bryan, Cong Zhu, Li Wang, Ifrah Tariq, Govinda M. Kamath, Ricardo De Matos Simoes, Eugen Dhimolea, Channing Yu, Yiguo Hu, Olli Dufva, Marios Giannakis, Vasilis Syrgkanis, Ernest Fraenkel, Todd Golub, Rizwan Romee, Satu Mustjoki, Aedin C. Culhane, Lotte Wieten, Constantine S. Mitsiades

Issue&Volume: 2021-07-12

Abstract: To systematically define molecular features in human tumor cells that determine their degree of sensitivity to human allogeneic natural killer (NK) cells, we quantified the NK cell responsiveness of hundreds of molecularly annotated ‘DNA-barcoded’ solid tumor cell lines in multiplexed format and applied genome-scale CRISPR-based gene-editing screens in several solid tumor cell lines, to functionally interrogate which genes in tumor cells regulate the response to NK cells. In these orthogonal studies, NK cell–sensitive tumor cells tend to exhibit ‘mesenchymal-like’ transcriptional programs; high transcriptional signature for chromatin remodeling complexes; high levels of B7-H6 (NCR3LG1); and low levels of HLA-E/antigen presentation genes. Importantly, transcriptional signatures of NK cell–sensitive tumor cells correlate with immune checkpoint inhibitor (ICI) resistance in clinical samples. This study provides a comprehensive map of mechanisms regulating tumor cell responses to NK cells, with implications for future biomarker-driven applications of NK cell immunotherapies.

DOI: 10.1038/s41588-021-00889-w

Source: https://www.nature.com/articles/s41588-021-00889-w

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex