CRISPR screening identifies the deubiquitylase ATXN3 as a PD-L1-positive regulator for tumor immune evasion.
CRISPR screening identifies the deubiquitylase ATXN3 as a PD-L1-positive regulator for tumor immune evasion.
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CRISPR筛选将去泛素化酶ATXN 3鉴定为肿瘤免疫逃避的PD-L1阳性调节剂。
DOI：
10.1172/jci167728
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发表时间：
2023-12-01
影响因子：
15.9
通讯作者：
Fang, Deyu
中科院分区：
文献类型：
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作者：
Wang, Shengnan;Iyer, Radhika;Han, Xiaohua;Wei, Juncheng;Li, Na;Cheng, Yang;Zhou, Yuanzhang;Gao, Qiong;Zhang, Lingqiang;Yan, Ming;Sun, Zhaolin;Fang, Deyu
调节肿瘤PD-L1的表达对于提高我们对肿瘤免疫逃避的理解和改进现有的抗肿瘤免疫疗法至关重要。在此，我们描述了一个基于crispr的筛选平台，并确定了ATXN3是PD-L1转录的正调节因子。TCGA数据库分析显示，在超过80%的人类癌症中，ATXN3和CD274呈正相关。肿瘤微环境因子，包括炎症细胞因子IFN-γ和缺氧，通过保护其下游转录因子IRF1、STAT3和HIF-2α，促进了atxn3诱导的Pd-l1转录。此外，ATNX3作为AP-1转录因子JunB的去泛素酶，表明ATNX3通过多种途径促进PD-L1的表达。在癌细胞中靶向删除ATXN3在很大程度上消除了IFN-γ和缺氧诱导的PD-L1表达，从而增强了小鼠的抗肿瘤免疫，这些作用部分被PD-L1重建逆转。此外，肿瘤ATXN3抑制提高了检查点阻断抗肿瘤免疫治疗的临床前疗效。重要的是，ATXN3在人肺腺癌和黑色素瘤中表达升高，且其表达水平与PD-L1及其转录因子IRF1和HIF-2α呈正相关。总的来说，我们的研究确定了我们认为是以前未知的去泛素酶ATXN3作为PD-L1转录的正调节因子，并为靶向ATXN3使检查点阻断抗肿瘤免疫治疗增敏提供了理论依据。
Regulation of tumoral PD-L1 expression is critical to advancing our understanding of tumor immune evasion and the improvement of existing antitumor immunotherapies. Herein, we describe a CRISPR-based screening platform and identified ATXN3 as a positive regulator for PD-L1 transcription. TCGA database analysis revealed a positive correlation between ATXN3 and CD274 in more than 80% of human cancers. ATXN3-induced Pd-l1 transcription was promoted by tumor microenvironmental factors, including the inflammatory cytokine IFN-γ and hypoxia, through protection of their downstream transcription factors IRF1, STAT3, and HIF-2α. Moreover, ATXN3 functioned as a deubiquitinase of the AP-1 transcription factor JunB, indicating that ATNX3 promotes PD-L1 expression through multiple pathways. Targeted deletion of ATXN3 in cancer cells largely abolished IFN-γ– and hypoxia-induced PD-L1 expression and consequently enhanced antitumor immunity in mice, and these effects were partially reversed by PD-L1 reconstitution. Furthermore, tumoral ATXN3 suppression improved the preclinical efficacy of checkpoint blockade antitumor immunotherapy. Importantly, ATXN3 expression was increased in human lung adenocarcinoma and melanoma, and its levels were positively correlated with PD-L1 as well as its transcription factors IRF1 and HIF-2α. Collectively, our study identifies what we believe to be a previously unknown deubiquitinase, ATXN3, as a positive regulator for PD-L1 transcription and provides a rationale for targeting ATXN3 to sensitize checkpoint blockade antitumor immunotherapy.