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
复制标题
Wnt 通路激活剂 TWS119 增强人 γ δ T 细胞抗结肠癌的增殖和细胞溶解活性
DOI：
10.1016/j.yexcr.2017.11.003
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发表时间：
2018-01-01
影响因子：
3.7
通讯作者：
Wang, Li-xin
中科院分区：
文献类型：
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作者：
Chen, Yong-qiang;Zheng, Lu;Wang, Li-xin
γδ T细胞是一类独特的T细胞亚群，在T细胞受体基因使用、组织嗜性和抗原识别方面展现出独特特征。过继性γδ T细胞转移疗法作为癌症免疫治疗中的一种有效方法，近来愈发受到重视。然而，由于细胞数量、活性和分化状态会使临床治疗效果大打折扣，利用γδ T细胞应答进行肿瘤免疫治疗颇具挑战。先前研究表明，Wnt/β-连环蛋白信号通路在T淋巴细胞的分化、存活及免疫应答增强方面发挥着关键作用。在本研究中，我们试图评估通过使用4,6 - 二取代吡咯并嘧啶（TWS119）抑制糖原合酶激酶-3β（GSK-3β）来激活Wnt/β-连环蛋白通路，是否能成为一种有效策略，以提高γδ T细胞针对结肠癌细胞的增殖、分化及细胞毒活性。值得注意的是，我们发现TWS119除了激活Wnt通路外，还通过激活雷帕霉素靶蛋白（mTOR）通路、上调抗凋亡蛋白Bcl-2的表达以及抑制裂解的半胱天冬酶-3，显著增强了γδ T细胞的增殖与存活。我们的研究结果还显示，在体外和体内，TWS119对γδ T细胞针对人结肠癌细胞的细胞毒活性的增强，主要与穿孔素和颗粒酶B表达的上调有关。此外，TWS119能够以剂量依赖的方式诱导CD62L或CCR5的表达，从而产生一群CD62L⁺γδ T细胞或CCR5⁺γδ T细胞。这些研究结果表明，TWS119可能是一种有用的辅助药物，可用于改善基于γδ T细胞的免疫治疗。
gamma delta T cells are a distinct T-cell subset that display unique characteristics regarding T-cell receptor gene usage, tissue tropism and antigen recognition. Adoptive gamma delta T cell transfer therapy has recently been gaining importance as an efficient approach in cancer immunotherapy. However, exploiting gamma delta T 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/beta-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/beta-catenin pathway through inhibition of glycogen synthase kinase-3 beta (GSK-3 beta) using 4,6-disubstituted pyrrolopyrimidine (TWS119) could be an efficient strategy to improve the proliferation, differentiation and cytolytic activity of gamma delta T cells against colon cancer cells. Remarkably, we found that TWS119 significantly enhanced the proliferation and survival of gamma delta T 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 gamma delta T 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(+)gamma delta T or CCR5(+)gamma delta T cells in a dosedependent manner. These findings suggested that TWS119 could be a useful complementary agent for improving gamma delta T cell-based immunotherapy.