MTOR inhibition potentiates cytotoxicity of Vγ4 γδ T cells via up-regulating NKG2D and TNF-α. Issue 5 (2nd June 2016)

• Record Type: Journal Article
• Authors: Cao, Guangchao; Wang, Qian; Li, Guangqiang; Meng, Ziyu; Liu, Hui; Tong, Jiyu; Huang, Wanjun; Liu, Zonghua; Jia, Yanqiong; Wei, Jun; Chi, Hongbo; Yang, Hengwen; Zhao, Liqing; Wu, Zhenzhou; Hao, Jianlei; Yin, Zhinan
• Is Part Of: Journal of leukocyte biology. Volume 100:Issue 5(2016)
• Page Start: 1181
• Page End: 1189
• Publication Date: 2016-06-02
• Subjects: rapamycin -- cytotoxicity -- STAT5; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.5A0116-053RR
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : Strategy to improve γδ T cells based cancer immunotherapy by suppressing mTOR signaling. Abstract: γδ T cells play a critical role in early anti-tumor immunity and perform cytotoxicity via NKG2D for recognition and multiple cytotoxic factors for tumor killing. Recent studies have demonstrated pivotal roles of mTOR-mediated metabolism in the maturation, differentiation, and effector function of diverse immune cells, including DCs, NK cells, CD4 + T cell subsets, and CD8 + T cells, but the role of mTOR signaling in γδ T cells is barely known. Here, we showed that suppressing mTOR signaling in in vitro-expanded Vγ4 γδ T cells via the mechanistic inhibitor rapamycin enhanced their cytotoxicity against multiple tumor cell lines, and these cells performed better tumor-suppressing effects upon adoptive therapy. Further investigation revealed that elevated cytotoxicity was a result of up-regulation of NKG2D and TNF-α. Moreover, rapamycin treatment significantly decreased the expression of CISH and increased pSTAT5. The inhibition of STAT5 pathways via siRNA interference or a specific inhibitor eliminated the up-regulation of NKG2D and TNF-α in rapamycin-treated Vγ4 γδ T cells. These results uncovered an important role of mTOR signaling in the cytotoxic effector function of γδ T cells and provided a potential strategy to improve γδ T cell-based cancer immunotherapy.