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Ho, Ping-Chih; Bihuniak, Jessica Dauz; Macintyre, Andrew N.; Staron, Matthew; Liu, Xiaojing; Amezquita, Robert; Tsui, Yao-Chen; Cui, Guoliang; Micevic, Goran; Perales, Jose C.; Kleinstein, Steven H.; Abel, E. Dale; Insogna, Karl L.; Feske, Stefan; Locasale, Jason W.; Bosenberg, Marcus W.; Rathmell, Jeffrey C.; Kaech, Susan M.
Cell, 09/2015, Letnik: 162, Številka: 6Journal Article
Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. We propose that a glucose-poor tumor microenvironment limits aerobic glycolysis in tumor-infiltrating T cells, which suppresses tumoricidal effector functions. We discovered a new role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining T cell receptor-mediated Ca2+-NFAT signaling and effector functions by repressing sarco/ER Ca2+-ATPase (SERCA) activity. Tumor-specific CD4 and CD8 T cells could be metabolically reprogrammed by increasing PEP production through overexpression of phosphoenolpyruvate carboxykinase 1 (PCK1), which bolstered effector functions. Moreover, PCK1-overexpressing T cells restricted tumor growth and prolonged the survival of melanoma-bearing mice. This study uncovers new metabolic checkpoints for T cell activity and demonstrates that metabolic reprogramming of tumor-reactive T cells can enhance anti-tumor T cell responses, illuminating new forms of immunotherapy. Display omitted •Glucose deprivation suppresses anti-tumor T cell effector functions•Glycolytic metabolite PEP sustains Ca2+ and NFAT signaling by blocking SERCA•Ca2+ signaling is an integrator of glycolytic activity and TCR signaling•T cell metabolic reprogramming enhances anti-tumor effector functions High rates of tumor cell glycolysis suppress intratumoral T cell function by depriving T cells of glucose and the downstream metabolite phosphoenolpyruvate (PEP), which is necessary for maximal Ca2+ -NFAT signaling in T cells. Metabolic rewiring of T cells to generate PEP in glucose-poor conditions improves their anti-tumor responses.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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