Cited by 1,462Cancer, Hypoxia, and MetabolismCancer Immunotherapy and BiomarkersT-cell and B-cell Immunology

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

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Ho, Ping-Chih, Bihuniak, Jessica Dauz, 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.·2015·Cell

DOI 10.1016/j.cell.2015.08.012PMC PMC4567953

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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.

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Authors: 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.
Affiliations: Yale University (US)
Duke University (US)
Cornell University (US)
Howard Hughes Medical Institute (US)
Institut d'Investigació Biomédica de Bellvitge (ES)
University of Iowa (US)
NYU Langone Health (US)
Corresponding author: Ho, Ping-Chih
Kaech, Susan M.
ORCID: Ho, Ping-Chih
Bihuniak, Jessica Dauz
Macintyre, Andrew N.
Liu, Xiaojing
Amezquita, Robert
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.
Venue: Cell
Publisher: Elsevier BV
Published: 2015-09
Volume: 162
Issue: 6
Pages: 1217-1228
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2015.08.012
PMC: PMC4567953
OpenAlex: W2160551785
Cited by: 1,462
References: 47
Citations by year: 2026: 125 · 2025: 148 · 2024: 127 · 2023: 147 · 2022: 155 · 2021: 168 · 2020: 156 · 2019: 116 · 2018: 116 · 2017: 110 · 2016: 84 · 2015: 10
FWCI: 35.25
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 375 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Howard Hughes Medical Institute
National Heart, Lung, and Blood Institute (R01HL108006)
National Cancer Institute (R00CA168997, R01CA123350, F30CA196089, P50CA121974, P30CA016359)
National Institute of General Medical Sciences (T32GM007205)
National Institute of Allergy and Infectious Diseases (R01AI110613, R37AI066232, R01AI063345, R01AI097302, R01AI074699, R01AI066232)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR053495)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: phosphoenolpyruvate, T cell metabolism, tumor-infiltrating T cells, aerobic glycolysis, tumor microenvironment, PCK1, SERCA, calcium signaling, NFAT, T cell effector function, metabolic reprogramming, antitumor immunity, melanoma, immunotherapy
MeSH terms: Animals, Calcium, Endoplasmic Reticulum, Glycolysis, Hexokinase, Immunotherapy, Melanoma, Phosphoenolpyruvate, Receptors, Antigen, T-Cell, Monitoring, Immunologic, Signal Transduction, CD4-Positive T-Lymphocytes, Transforming Growth Factor beta, Lymphocytes, Tumor-Infiltrating, NFATC Transcription Factors, Mice, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Tumor Microenvironment

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

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