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

doi:10.1016/j.cell.2015.08.012

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

Journal article

Open access

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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, …

Cell (Cambridge), Vol.162(6), pp.1217-1228

09/10/2015

DOI: 10.1016/j.cell.2015.08.012

PMCID: PMC4567953

PMID: 26321681

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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.

Signal Transduction

Immunotherapy

Transforming Growth Factor beta - immunology

Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism

Receptors, Antigen, T-Cell - metabolism

Calcium - metabolism

Monitoring, Immunologic

NFATC Transcription Factors - metabolism

Endoplasmic Reticulum - metabolism

Tumor Microenvironment

CD4-Positive T-Lymphocytes - immunology

Phosphoenolpyruvate - metabolism

Animals

Melanoma - immunology

Glycolysis

Mice

Hexokinase - metabolism

Melanoma - therapy

Lymphocytes, Tumor-Infiltrating - immunology

Details

Title: Subtitle: Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses
Creators: Ping-Chih Ho - Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA. Electronic address: ping-chih.ho@unil.ch
Jessica Dauz Bihuniak - Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA
Andrew N Macintyre - Department of Pharmacology and Cancer Biology, Immunology, Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
Matthew Staron - Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
Xiaojing Liu - Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
Robert Amezquita - 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
Yao-Chen Tsui - Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
Guoliang Cui - Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
Goran Micevic - Department of Dermatology, Yale University School of Medicine, New Haven, CT 06519, USA
Jose C Perales - Biophysics Unit, Department of Physiological Sciences II, IDIBELL-University of Barcelona, Fexia Llarga s/n 08907, Spain
Steven H Kleinstein - Department of Pathology, Yale University School of Medicine, New Haven, CT 06519, USA
E Dale Abel - 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
Karl L Insogna - Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA
Stefan Feske - Department of Pathology, New York University Langone Medical Center, New York, NY 10016, USA
Jason W Locasale - Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
Marcus W Bosenberg - 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
Jeffrey C Rathmell - Department of Pharmacology and Cancer Biology, Immunology, Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
Susan M Kaech - 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
Resource Type: Journal article
Publication Details: Cell (Cambridge), Vol.162(6), pp.1217-1228
Publisher: United States
DOI: 10.1016/j.cell.2015.08.012
PMID: 26321681
PMCID: PMC4567953
ISSN: 0092-8674
eISSN: 1097-4172
Grant note: 5 P50 CA121974 / NCI NIH HHS R37AI066232 / NIAID NIH HHS R00 CA168997 / NCI NIH HHS R01 AI110613 / NIAID NIH HHS P30 AR053495 / NIAMS NIH HHS Howard Hughes Medical Institute F30 CA196089 / NCI NIH HHS R01 AI063345 / NIAID NIH HHS R01 AI097302 / NIAID NIH HHS P50 CA121974 / NCI NIH HHS R01 CA123350 / NCI NIH HHS R37 AI066232 / NIAID NIH HHS R00CA168997 / NCI NIH HHS R01 HL108006 / NHLBI NIH HHS R01AI074699 / NIAID NIH HHS P30 CA016359 / NCI NIH HHS R01AI110613 / NIAID NIH HHS T32 GM007205 / NIGMS NIH HHS R01 AI066232 / NIAID NIH HHS R01 AI074699 / NIAID NIH HHS R01HL108006 / NHLBI NIH HHS
Language: English
Date published: 09/10/2015
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024502702771

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