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

• Published in: Cell Vol. 162; no. 6; pp. 1217 - 1228
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.09.2015
• Subjects: Animals; Ca2-transporting ATPase; Calcium - metabolism; CD4-Positive T-Lymphocytes - immunology; CD8-positive T-lymphocytes; Endoplasmic Reticulum - metabolism; Glycolysis; Hexokinase - metabolism; Immunotherapy; Lymphocytes, Tumor-Infiltrating - immunology; Melanoma - immunology; Melanoma - therapy; metabolites; Mice; Monitoring, Immunologic; NFATC Transcription Factors - metabolism; Phosphoenolpyruvate - metabolism; Receptors, Antigen, T-Cell - metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Signal Transduction; Transforming Growth Factor beta - immunology; Tumor Microenvironment
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2015.08.012

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.