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

• Published in: Nature communications Vol. 12; no. 1; pp. 2346 - 14
• Main Authors: Wu, Youqian, Zhang, Chao, Liu, Xiaolan, He, Zhengfu, Shan, Bing, Zeng, Qingxin, Zhao, Qingwei, Zhu, Huaying, Liao, Hongwei, Cen, Xufeng, Xu, Xiaoyan, Zhang, Mengmeng, Hou, Tingjun, Wang, Zhe, Yan, Huanhuan, Yang, Shuying, Sun, Yaqin, Chen, Yanying, Wu, Ronghai, Xie, Tingxue, Chen, Wei, Najafov, Ayaz, Ying, Songmin, Xia, Hongguang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20-04-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/31; 13/51; 13/89; 13/95; 49; 631/337; 631/80; 64; 64/60; 82/83; Animals; B7-H1 Antigen - chemistry; B7-H1 Antigen - metabolism; Cancer; Cell activation; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 protein; Cytotoxicity; Degradation; Drug screening; Drug Screening Assays, Antitumor; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; Female; Glycogen Synthase Kinase 3 - metabolism; HEK293 Cells; High-Throughput Screening Assays; Humanities and Social Sciences; Humans; Immunity; Immunotherapy; Immunotherapy - methods; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Biological; multidisciplinary; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - therapy; PD-L1 protein; Phosphorylation; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Proteolysis; Science; Science (multidisciplinary); Signal Transduction; Signaling; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Therapeutic targets; Tumor Escape - physiology; U937 Cells; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Ubiquitination - drug effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22467-8

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.
The regulation of PD-L1 via proteasomal degradation is unclear. Here, the authors show that EGFR inhibition activates GSK3 α to promote PD-L1 phosphorylation, which leads to PD-L1 ubiquitination and proteasome mediated degradation by ARIH1 E3 ligase.