2. Academic Validation
  3. 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

  • Nat Commun. 2021 Apr 20;12(1):2346. doi: 10.1038/s41467-021-22467-8.
Youqian Wu # 1,  Chao Zhang # 2 3,  Xiaolan Liu # 1,  Zhengfu He # 4,  Bing Shan 5,  Qingxin Zeng 4,  Qingwei Zhao 1,  Huaying Zhu 6,  Hongwei Liao 7,  Xufeng Cen 1,  Xiaoyan Xu 1,  Mengmeng Zhang 5,  Tingjun Hou 8,  Zhe Wang 8,  Huanhuan Yan 1,  Shuying Yang 1,  Yaqin Sun 1,  Yanying Chen 1,  Ronghai Wu 1,  Tingxue Xie 1,  Wei Chen 6,  Ayaz Najafov 9,  Songmin Ying 10 11,  Hongguang Xia 12 13
Affiliations

Affiliations

  • 1 Department of Biochemistry and Research Center of Clinical Pharmacy of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 2 International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, 322000, China.
  • 3 Key Laboratory Respiratory Disease of Zhejiang Province, Department of Anatomy and Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
  • 4 Department of Thoracic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.
  • 5 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 6 Department of Cell Biology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 7 Key Laboratory Respiratory Disease of Zhejiang Province, Department of Pharmacology and Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
  • 8 Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 9 Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA. ayaz_najafov@hms.harvard.edu.
  • 10 International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, 322000, China. yings@zju.edu.cn.
  • 11 Key Laboratory Respiratory Disease of Zhejiang Province, Department of Pharmacology and Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China. yings@zju.edu.cn.
  • 12 Department of Biochemistry and Research Center of Clinical Pharmacy of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China. hongguangxia@zju.edu.cn.
  • 13 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China. hongguangxia@zju.edu.cn.
  • # Contributed equally.
PMID: 33879767 DOI: 10.1038/s41467-021-22467-8
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.

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