Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8451600 | Experimental Cell Research | 2018 | 9 Pages |
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
CFSECCR5PBMCsIFN-γPVDFγδT cellsGSK-3βrhIL-2APCsmTORACTWnt/β-CateninAntigen presenting cellsimmunotherapyinterferon-γrecombinant human interleukin-2adoptive cell therapypolyvinylidene difluorideColorectal cancerColon cancerperipheral blood mononuclear cellslactate dehydrogenaseLDHCARmajor histocompatibility complexMHCmammalian target of rapamycinCRCcarboxyfluorescein succinimidyl esterGlycogen synthase kinase-3βchimeric antigen receptor
Related Topics
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Biochemistry, Genetics and Molecular Biology
Cancer Research
Authors
Yong-qiang Chen, Lu Zheng, Mohanad Aldarouish, Zhong-hai Zhou, Ning Pan, Jun-quan Liu, Fu-xing Chen, Li-xin Wang,