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.
Keywords:
STAT5; cytotoxicity; rapamycin.
© Society for Leukocyte Biology.
MeSH terms
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Animals
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Cell Line, Tumor
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Coculture Techniques
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Cytotoxicity, Immunologic
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Gene Expression Regulation / drug effects
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Immunotherapy, Adoptive
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Melanoma, Experimental / immunology*
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Melanoma, Experimental / pathology
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Melanoma, Experimental / therapy
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Mice
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Mice, Knockout
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NK Cell Lectin-Like Receptor Subfamily K / biosynthesis*
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NK Cell Lectin-Like Receptor Subfamily K / genetics
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RNA Interference
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RNA, Small Interfering / genetics
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Receptors, Antigen, T-Cell, gamma-delta* / deficiency
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Receptors, Antigen, T-Cell, gamma-delta* / genetics
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STAT5 Transcription Factor / antagonists & inhibitors
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / physiology
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Sirolimus / pharmacology
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Specific Pathogen-Free Organisms
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / immunology*
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T-Lymphocytes, Cytotoxic / drug effects
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T-Lymphocytes, Cytotoxic / immunology*
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / physiology
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Tumor Necrosis Factor-alpha / biosynthesis*
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Tumor Necrosis Factor-alpha / genetics
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Up-Regulation / drug effects
Substances
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Klrk1 protein, mouse
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NK Cell Lectin-Like Receptor Subfamily K
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RNA, Small Interfering
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Receptors, Antigen, T-Cell, gamma-delta
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STAT5 Transcription Factor
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Stat5a protein, mouse
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Tumor Necrosis Factor-alpha
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mTOR protein, mouse
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TOR Serine-Threonine Kinases
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Sirolimus