ALKBH5 promotes PD-L1-mediated immune escape through m6A modification of ZDHHC3 in glioma.
ALKBH5 promotes PD-L1-mediated immune escape through m6A modification of ZDHHC3 in glioma.
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ALKBH5 通过 m6A 修饰 ZDHHC3 促进胶质瘤中 PD-L1 介导的免疫逃逸
DOI：
10.1038/s41420-022-01286-w
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发表时间：
2022-12-24
影响因子：
7
通讯作者：
Guo H
中科院分区：
文献类型：
--
作者：
Tang W;Xu N;Zhou J;He Z;Lenahan C;Wang C;Ji H;Liu B;Zou Y;Zeng H;Guo H
腺苷n6甲基化（m6A）是真核rna中最常见的化学修饰之一，在肿瘤的发生和发展中起着至关重要的作用。最近，新的研究表明，ALKBH5修饰m6A与各种类型癌症的免疫治疗反应有关。然而，m6A去甲基化酶ALKBH5是否参与调节肿瘤免疫微环境以及免疫治疗胶质母细胞瘤的疗效尚不清楚。本研究发现，缺失ALKBH5可显著抑制同种胶质瘤移植物的生长，恢复抗肿瘤免疫反应，增加脑脊液中细胞毒性淋巴细胞浸润和促炎细胞因子，同时显著抑制PD-L1蛋白表达。m6a甲基化RNA免疫沉淀测序和RNA测序鉴定ZDDHC3是ALKBH5的直接靶点。机械上，ALKBH5缺乏会损害ythdf2介导的ZDHHC3 mRNA的稳定性，从而通过加速胶质瘤中PD-L1的降解来抑制PD-L1的表达。此外，IOX1基因缺失或药理抑制ALKBH5可增强临床前小鼠模型抗pd -1治疗的疗效。这些数据表明，联合抗pd -1治疗和抑制ALKBH5可能是一种很有前途的治疗胶质瘤的策略。
N6-methylation of adenosine (m6A) is one of the most frequent chemical modifications in eukaryotic RNAs and plays a vital role in tumorigenesis and progression. Recently, emerging studies have shown that m6A modification by ALKBH5 was associated with immunotherapy response in various types of cancer. However, whether m6A demethylases ALKBH5 participate in regulating the tumor immune microenvironment and the efficacy of immunotherapy in glioblastoma remain unknown. Here, we found that deletion of ALKBH5 significantly inhibited the growth of glioma allografts, rescued the antitumoral immune response, and increased cytotoxic lymphocyte infiltration and proinflammatory cytokines in CSF while significantly suppressing PD-L1 protein expression. m6A-methylated RNA immunoprecipitation sequencing and RNA sequencing identify ZDDHC3 as the direct target of ALKBH5. Mechanically, ALKBH5 deficiency impairs the YTHDF2-mediated stability of ZDHHC3 mRNA, thereby suppressing PD-L1 expression by accelerating PD-L1 degradation in glioma. In addition, genetic deletion or pharmacological inhibition of ALKBH5 with IOX1 enhances the therapeutic efficacy of anti-PD-1 treatment in preclinical mice models. These data suggest that the combination of anti-PD-1 therapy and ALKBH5 inhibition may be a promising treatment strategy in glioma.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
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作者：
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发表时间：
2016-06-17
期刊：
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影响因子：
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DOI：
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发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
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作者：
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发表时间：
2020-01
期刊：
Nature reviews. Immunology
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作者：
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通讯作者：
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DOI：
10.1158/1078-0432.ccr-16-3215
发表时间：
2017-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
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