ARIH1 signaling promotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation.
ARIH1 signaling promotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation.
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ARIH1 信号通过靶向 PD-L1 进行蛋白酶体降解来促进抗肿瘤免疫
DOI：
10.1038/s41467-021-22467-8
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发表时间：
2021-04-20
影响因子：
16.6
通讯作者：
Xia H
中科院分区：
文献类型：
--
作者：
Wu Y;Zhang C;Liu X;He Z;Shan B;Zeng Q;Zhao Q;Zhu H;Liao H;Cen X;Xu X;Zhang M;Hou T;Wang Z;Yan H;Yang S;Sun Y;Chen Y;Wu R;Xie T;Chen W;Najafov A;Ying S;Xia H
PD-L1的癌症表达抑制抗肿瘤免疫。PD-L1已成为一个引人注目的治疗靶点。然而，PD-L1降解的调控尚不清楚。在这里，我们使用高通量药物筛选确定了几种化合物作为PD-L1降解的诱导剂。我们发现EGFR抑制剂促进了GSK 3 α介导的Ser 279/Ser 283磷酸化后的PD-L1泛素化和蛋白酶体降解。我们确定ARIH 1为负责靶向PD-L1降解的E3泛素连接酶。ARIH 1的过表达在野生型小鼠中抑制肿瘤生长并促进细胞毒性T细胞活化，但在免疫功能低下的小鼠中则不然，这突出了ARIH 1在抗肿瘤免疫中的作用。此外，EGFR抑制剂ES-072与抗CTLA 4免疫疗法的组合导致对肿瘤生长和细胞毒性T细胞活化的累加效应。我们的研究结果描述了PD-L1降解和癌症通过EGFR-GSK 3 α-ARIH 1信号转导逃避免疫的机制，并表明GSK 3 α和ARIH 1可能是增强抗肿瘤免疫和增强免疫治疗的潜在药物靶点。
Cancer expression of PD-L1 suppresses anti-tumor immunity. PD-L1 has emerged as a remarkable therapeutic target. However, the regulation of PD-L1 degradation is not understood. Here, we identify several compounds as inducers of PD-L1 degradation using a high-throughput drug screen. We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation. Overexpression of ARIH1 suppresses tumor growth and promotes cytotoxic T cell activation in wild-type, but not in immunocompromised mice, highlighting the role of ARIH1 in anti-tumor immunity. Moreover, combining EGFR inhibitor ES-072 with anti-CTLA4 immunotherapy results in an additive effect on both tumor growth and cytotoxic T cell activation. Our results delineate a mechanism of PD-L1 degradation and cancer escape from immunity via EGFR-GSK3α-ARIH1 signaling and suggest GSK3α and ARIH1 might be potential drug targets to boost anti-tumor immunity and enhance immunotherapies.
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影响因子：
3.9
作者：
Abdelhamed S;Ogura K;Yokoyama S;Saiki I;Hayakawa Y
通讯作者：
Hayakawa Y
DOI：
10.1158/1078-0432.ccr-15-3101
发表时间：
2016-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Gainor JF;Shaw AT;Sequist LV;Fu X;Azzoli CG;Piotrowska Z;Huynh TG;Zhao L;Fulton L;Schultz KR;Howe E;Farago AF;Sullivan RJ;Stone JR;Digumarthy S;Moran T;Hata AN;Yagi Y;Yeap BY;Engelman JA;Mino-Kenudson M
通讯作者：
Mino-Kenudson M
影响因子：
7.3
作者：
Gibbons Johnson RM;Dong H
通讯作者：
Dong H
影响因子：
11.4
作者：
Kelsall, Ian R.;Duda, David M.;Olszewski, Jennifer L.;Hofmann, Kay;Knebel, Axel;Langevin, Frederic;Wood, Nicola;Wightman, Melanie;Schulman, Brenda A.;Alpi, Arno F.
通讯作者：
Alpi, Arno F.
影响因子：
--
作者：
Cervello, Melchiorre;Augello, Giuseppa;Montalto, Giuseppe
通讯作者：
Montalto, Giuseppe