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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1217-1228
Number of pages12
JournalCell
Volume162
Issue number6
DOIs
StatePublished - Feb 11 2015

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Phosphoenolpyruvate
T-cells
Tumors
T-Lymphocytes
Neoplasms
Glycolysis
Bearings (structural)
Tumor Microenvironment
Calcium-Transporting ATPases
Growth
Metabolites
T-Cell Antigen Receptor
Thomsen-Friedenreich antibodies
Metabolism
Immunotherapy
Melanoma
Glucose

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ho, P. C., Bihuniak, J., MacIntyre, A. N., Staron, M., Liu, X., Amezquita, R., ... Kaech, S. M. (2015). Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell, 162(6), 1217-1228. https://doi.org/10.1016/j.cell.2015.08.012

Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. / Ho, Ping Chih; Bihuniak, Jessica; 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.

In: Cell, Vol. 162, No. 6, 11.02.2015, p. 1217-1228.

Research output: Contribution to journalArticle

Ho, PC, Bihuniak, J, MacIntyre, AN, Staron, M, Liu, X, Amezquita, R, Tsui, YC, Cui, G, Micevic, G, Perales, JC, Kleinstein, SH, Abel, ED, Insogna, KL, Feske, S, Locasale, JW, Bosenberg, MW, Rathmell, JC & Kaech, SM 2015, 'Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses', Cell, vol. 162, no. 6, pp. 1217-1228. https://doi.org/10.1016/j.cell.2015.08.012
Ho PC, Bihuniak J, MacIntyre AN, Staron M, Liu X, Amezquita R et al. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell. 2015 Feb 11;162(6):1217-1228. https://doi.org/10.1016/j.cell.2015.08.012
Ho, Ping Chih ; Bihuniak, Jessica ; 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. / Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. In: Cell. 2015 ; Vol. 162, No. 6. pp. 1217-1228.
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