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

Ping Chih Ho, Jessica Dauz 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 - Sep 10 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses'. Together they form a unique fingerprint.

  • Cite this

    Ho, P. C., Bihuniak, J. D., MacIntyre, A. N., Staron, M., Liu, X., Amezquita, R., Tsui, Y. C., Cui, G., Micevic, G., Perales, J. C., Kleinstein, S. H., Abel, E. D., Insogna, K. L., Feske, S., Locasale, J. W., Bosenberg, M. W., Rathmell, J. C., & 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