Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses.
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 Ca(2+)-NFAT signaling and effector functions by repressing sarco/ER Ca(2+)-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.
Ho, P-C; Bihuniak, JD; Macintyre, AN; Staron, M; Liu, X; Amezquita, R; Tsui, Y-C; Cui, G; Micevic, G; Perales, JC; Kleinstein, SH; Abel, ED; Insogna, KL; Feske, S; Locasale, JW; Bosenberg, MW; Rathmell, JC; Kaech, SM
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