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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • September 10, 2015

Published In

Volume / Issue

  • 162 / 6

Start / End Page

  • 1217 - 1228

PubMed ID

  • 26321681

Pubmed Central ID

  • PMC4567953

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2015.08.012


  • eng

Conference Location

  • United States