Format

Send to

Choose Destination
Cell. 2015 Sep 10;162(6):1217-28. doi: 10.1016/j.cell.2015.08.012. Epub 2015 Aug 27.

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

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA. Electronic address: ping-chih.ho@unil.ch.
2
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
3
Department of Pharmacology and Cancer Biology, Immunology, Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA.
4
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.
5
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
6
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06519, USA.
7
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
8
Department of Dermatology, Yale University School of Medicine, New Haven, CT 06519, USA.
9
Biophysics Unit, Department of Physiological Sciences II, IDIBELL-University of Barcelona, Fexia Llarga s/n 08907, Spain.
10
Department of Pathology, Yale University School of Medicine, New Haven, CT 06519, USA.
11
Fraternal Order of Eagles Diabetes Research Center, Division of Endocrinology and Metabolism, Department of Medicine, Carver College of Medicine University of Iowa, Iowa City, IA 52242, USA.
12
Department of Pathology, New York University Langone Medical Center, New York, NY 10016, USA.
13
Department of Pathology, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06519, USA.
14
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: susan.kaech@yale.edu.

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 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.

PMID:
26321681
PMCID:
PMC4567953
DOI:
10.1016/j.cell.2015.08.012
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center