Cell
Volume 162, Issue 6, 10 September 2015, Pages 1217-1228
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Article
Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses

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Highlights

  • 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

Summary

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.

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