ARIH1 signaling promotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation

Youqian Wu, Chao Zhang, Xiaolan Liu, Zhengfu He, Bing Shan, Qingxin Zeng, Qingwei Zhao, Huaying Zhu, Hongwei Liao, Xufeng Cen, Xiaoyan Xu, Mengmeng Zhang, Tingjun Hou, Zhe Wang, Huanhuan Yan, Shuying Yang, Yaqin Sun, Yanying Chen, Ronghai Wu, Tingxue Xie, Wei Chen, Ayaz Najafov (), Songmin Ying () and Hongguang Xia ()
Additional contact information
Youqian Wu: Zhejiang University School of Medicine
Chao Zhang: The Fourth Affiliated Hospital of Zhejiang University School of Medicine
Xiaolan Liu: Zhejiang University School of Medicine
Zhengfu He: Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University
Bing Shan: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Qingxin Zeng: Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University
Qingwei Zhao: Zhejiang University School of Medicine
Huaying Zhu: Zhejiang University School of Medicine
Hongwei Liao: Zhejiang University School of Medicine
Xufeng Cen: Zhejiang University School of Medicine
Xiaoyan Xu: Zhejiang University School of Medicine
Mengmeng Zhang: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Tingjun Hou: Zhejiang University
Zhe Wang: Zhejiang University
Huanhuan Yan: Zhejiang University School of Medicine
Shuying Yang: Zhejiang University School of Medicine
Yaqin Sun: Zhejiang University School of Medicine
Yanying Chen: Zhejiang University School of Medicine
Ronghai Wu: Zhejiang University School of Medicine
Tingxue Xie: Zhejiang University School of Medicine
Wei Chen: Zhejiang University School of Medicine
Ayaz Najafov: Harvard Medical School
Songmin Ying: The Fourth Affiliated Hospital of Zhejiang University School of Medicine
Hongguang Xia: Zhejiang University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22467-8

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