1. Academic Validation
  2. Wnt pathway activator TWS119 enhances the proliferation and cytolytic activity of human γδT cells against colon cancer

Wnt pathway activator TWS119 enhances the proliferation and cytolytic activity of human γδT cells against colon cancer

  • Exp Cell Res. 2018 Jan 1;362(1):63-71. doi: 10.1016/j.yexcr.2017.11.003.
Yong-Qiang Chen 1 Lu Zheng 2 Mohanad Aldarouish 3 Zhong-Hai Zhou 2 Ning Pan 4 Jun-Quan Liu 2 Fu-Xing Chen 2 Li-Xin Wang 5
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing, Jiangsu Province 210009, People's Republic of China; Department of Central Laboratory, 97th Hospital of PLA, 226 Tongshang Road, Xuzhou, Jiangsu Province 221004, People's Republic of China.
  • 2 Department of Central Laboratory, 97th Hospital of PLA, 226 Tongshang Road, Xuzhou, Jiangsu Province 221004, People's Republic of China.
  • 3 Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing, Jiangsu Province 210009, People's Republic of China; Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province 210009, People's Republic of China.
  • 4 Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing, Jiangsu Province 210009, People's Republic of China.
  • 5 Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing, Jiangsu Province 210009, People's Republic of China. Electronic address: lxwang@seu.edu.cn.
Abstract

γδT cells are a distinct T-cell subset that display unique characteristics regarding T-cell receptor gene usage, tissue tropism and antigen recognition. Adoptive γδT cell transfer therapy has recently been gaining importance as an efficient approach in Cancer Immunotherapy. However, exploiting γδT cell response for tumour immunotherapy is a challenge due to cell numbers, activities and differentiation states that minimize the clinical therapeutic effects. Previous studies have indicated that the Wnt/β-catenin signalling pathway plays a crucial role in the differentiation, survival and enhancement of the immune response of T lymphocytes. In this study, we sought to evaluate whether the activation of the Wnt/β-catenin pathway through inhibition of glycogen synthase kinase-3β (GSK-3β) using 4,6-disubstituted pyrrolopyrimidine (TWS119) could be an efficient strategy to improve the proliferation, differentiation and cytolytic activity of γδT cells against colon Cancer cells. Remarkably, we found that TWS119 significantly enhanced the proliferation and survival of γδT cells via activation of the mammalian target of rapamycin (mTOR) pathway, upregulation of the expression of the anti-apoptotic protein Bcl-2 and inhibition of cleaved Caspase-3 in addition to the Wnt pathway. Our results also showed that enhancement of the cytolytic activity of γδT cells against human colon Cancer cells by TWS119 was chiefly associated with upregulation of the expression of perforin and granzyme B in vitro and in vivo. Additionally, TWS119 can induce the expression of CD62L or CCR5 to generate a population of CD62L+γδT or CCR5+γδT cells in a dose-dependent manner. These findings suggested that TWS119 could be a useful complementary agent for improving γδT cell-based immunotherapy.

Keywords

Colon cancer; Immunotherapy; TWS119; Wnt/β-Catenin; γδT cells.

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