Original Articles
Mingxia Zhao, Wenjie Guo, Yuanyuan Wu, Chenxi Yang, Liang Zhong, Guoliang Deng, Yuyu Zhu, Wen Liu, Yanhong Gu, Yin Lu, Lingdong Kong, Xiangbao Meng, Qiang Xu, Yang Sun. SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade[J]. Acta Pharmaceutica Sinica B, 2019, 9(2): 304-315

SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade
Mingxia Zhaoa, Wenjie Guoa, Yuanyuan Wub, Chenxi Yanga, Liang Zhongc, Guoliang Denga, Yuyu Zhua, Wen Liua, Yanhong Gud, Yin Lub, Lingdong Konga, Xiangbao Menga,c, Qiang Xua, Yang Suna
a State Key Laboratory of Pharmaceutical Biotechnology, Deparment of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China;
b Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China;
c State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China;
d Department of Oncology, the First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China
Abstract:
Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo. However, whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099. Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system. SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8+IFN-γ+ T cells and the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin, which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and antiPD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.
Key words:    Cancer immunotherapy    SHP2    SHP099    PD-1    Colon cancer   
Received: 2018-07-16     Revised: 2018-08-18
DOI: 10.1016/j.apsb.2018.08.009
Funds: We thank Dr.Chong Sun (The Netherlands Cancer Institute,The Netherlands) for valuable advice on this project.This work was supported by National Natural Science Foundation of China (Nos.81673436,21472091,81872877,81673437),Mountain-Climbing Talents Project of Nanjing University,the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University (No.KF-GN-201703,China),Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica (No.JKLPSE201802,China) and the Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD,China).
Corresponding author: Xiangbao Meng, Qiang Xu, Yang Sun     Email:xbmeng@bjmu.edu.cn;molpharm@163.com;yangsun@nju.edu.cn
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Authors
Mingxia Zhao
Wenjie Guo
Yuanyuan Wu
Chenxi Yang
Liang Zhong
Guoliang Deng
Yuyu Zhu
Wen Liu
Yanhong Gu
Yin Lu
Lingdong Kong
Xiangbao Meng
Qiang Xu
Yang Sun

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