Genome-Wide CRISPR Screening Identifies JAK1 Deficiency as a Mechanism of T-Cell Resistance
Genome-Wide CRISPR Screening Identifies JAK1 Deficiency as a Mechanism of T-Cell Resistance
复制标题
全基因组 CRISPR 筛选确定 JAK1 缺陷是 T 细胞耐药机制
DOI：
10.3389/fimmu.2019.00251
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发表时间：
2019-02-19
影响因子：
7.3
通讯作者：
Yang, Xuanming
中科院分区：
文献类型：
--
作者：
Han, Ping;Dai, Qiang;Yang, Xuanming
体细胞基因突变在肿瘤的免疫逃逸中起着关键作用。然而，关于黑色素瘤免疫治疗抵抗的基因的信息有限。为了回答这个问题，我们通过聚集规则间隔短回文重复序列(CRISPR)/CRISPR相关蛋白-9核酸酶技术建立了一个全基因组敲除的B16/卵清蛋白细胞系，并通过体内过继OT-I T细胞转移和体外OT-I T细胞杀伤实验确定Janus Kinase(JAK)1缺乏通过两步机制介导T细胞耐药。JAK1的缺失降低了肿瘤细胞中的JAK信号转导和转录激活信号--导致肿瘤对T细胞效应分子干扰素的抵抗--并通过损害抗原提呈而抑制T细胞的激活。这些发现为探索癌症的免疫治疗耐药性提供了一种新的方法，并确定JAK1是治疗黑色素瘤的潜在治疗靶点。
Somatic gene mutations play a critical role in immune evasion by tumors. However, there is limited information on genes that confer immunotherapy resistance in melanoma. To answer this question, we established a whole-genome knockout B16/ovalbumin cell line by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease technology, and determined by in vivo adoptive OT-I T-cell transfer and an in vitro OT-I T-cell-killing assay that Janus kinase (JAK)1 deficiency mediates T-cell resistance via a two-step mechanism. Loss of JAK1 reduced JAK-Signal transducer and activator of transcription signaling in tumor cells—resulting in tumor resistance to the T-cell effector molecule interferon—and suppressed T-cell activation by impairing antigen presentation. These findings provide a novel method for exploring immunotherapy resistance in cancer and identify JAK1 as potential therapeutic target for melanoma treatment.