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Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses

2015; Cell Press; Volume: 162; Issue: 6 Linguagem: Inglês

10.1016/j.cell.2015.08.012

1097-4172

Ping‐Chih Ho, Jessica Bihuniak, Andrew N. Macintyre, Matthew Staron, Xiaojing Liu, Robert A. Amezquita, Yao-Chen Tsui, Guoliang Cui, Goran Micevic, José C. Perales, Steven H. Kleinstein, E. Dale Abel, Karl Insogna, Stefan Feske, Jason W. Locasale, Marcus Bosenberg, Jeffrey C. Rathmell, Susan M. Kaech,

Immune Cell Function and Interaction

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.