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 XieWei Chen, Ayaz Najafov, Songmin Ying, Hongguang Xia

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Article number2346
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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