title: mTOR inhibition potentiates cytotoxicity of Vγ4 γδ T cells via up-regulating NKG2D and TNF-α.
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.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Guangchao
authors.initials: G
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, China; and.
authors.forename: Guangqiang
authors.initials: G
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Ziyu
authors.initials: Z
authors.lastname: Meng
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, China; and.
authors.forename: Jiyu
authors.initials: J
authors.lastname: Tong
authors.affiliation: Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, China; and.
authors.forename: Wanjun
authors.initials: W
authors.lastname: Huang
authors.affiliation: Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, China; and.
authors.forename: Zonghua
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, China; and.
authors.forename: Yanqiong
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
authors.affiliation: Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, China; and.
authors.forename: Hengwen
authors.initials: H
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Liqing
authors.initials: L
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, China; and jianlei.hao@yale.edu.
authors.forename: Jianlei
authors.initials: J
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China; zhinan.yin@yale.edu.|Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, China; and.
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Yin
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D005786:Gene Expression Regulation / Q000187:drug effects; D016219:Immunotherapy, Adoptive; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis* / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034741:RNA, Small Interfering; D016692:Receptors, Antigen, T-Cell, gamma-delta; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: STAT5; cytotoxicity; rapamycin