Original articles
Zhiru Wang, Wenting Kang, Ouwen Li, Fengyu Qi, Junwei Wang, Yinghua You, Pengxing He, Zhenhe Suo, Yichao Zheng, Hong-Min Liu. Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing[J]. Acta Pharmaceutica Sinica B, 2021, 11(3): 694-707

Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing
Zhiru Wanga,b, Wenting Kanga, Ouwen Lia, Fengyu Qia, Junwei Wanga, Yinghua Youa, Pengxing Hea, Zhenhe Suob, Yichao Zhenga, Hong-Min Liua
a School of Pharmaceutical Sciences, Zhengzhou University Co-Innovation Center of Henan Province for New Drug R&D and Preclinical Safety State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou 450001 China;
b Department of Pathology, the Norwegian Radium Hospital, Oslo University Hospital Department of Pathology, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo 0379, Norway
Targeting immune checkpoints such as programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for treating melanoma, gastric cancer (GC) and bladder cancer with clinical benefit. Nevertheless, many patients failed to respond to anti-PD-1/PD-L1 treatment, so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy. Here with the data from The Cancer Genome Atlas (TCGA) and our in-house tissue library, PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7 (USP7) in GC. Furthermore, USP7 directly interacted with PD-L1 in order to stabilize it,while abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing in vitro and in vivo. Besides, USP7 inhibitor suppressed GC cells proliferation by stabilizing P53 in vitro and in vivo. Collectively, our findings indicate that in addition to inhibiting cancer cells proliferation, USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously. Hence, these data posit USP7 inhibitor as an anti-proliferation agent as well as a novel therapeutic agent in PD-L1/PD-1 blockade strategy that can promote the immune response of the tumor.
Key words:    USP7    PD-L1    Epigenetics    Immunotherapy    Ubiquitination    Gastric cancer    Immunosuppression    Cancer biology   
Received: 2020-06-21     Revised: 2020-09-01
DOI: 10.1016/j.apsb.2020.11.005
Funds: The authors thank Dr. Timothy Harrison for USP7 inhibitor Almac4. This work was supported by National Natural Science Foundation of China (Project No. 81602961 for Yichao Zheng;Nos. 81430085, 81773562, and 82020108030 for Hongmin Liu); National Key Research Program of Proteins (Nos. 2016YFA0501800 and 2018YFE0195100 for Hongmin Liu, China); Key Research Program of Henan Province (No. 161100310100, for Hongmin Liu, China). Science and Technology Innovation Talents of Henan Provincial Education Department (19IRTSTHN001, China).
Corresponding author: Yichao Zheng, Hong-Min Liu     Email:liuhm@zzu.edu.cn;yichaozheng@zzu.edu.cn
Author description:
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Zhiru Wang
Wenting Kang
Ouwen Li
Fengyu Qi
Junwei Wang
Yinghua You
Pengxing He
Zhenhe Suo
Yichao Zheng
Hong-Min Liu

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