Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses
Open accessAbstract
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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High expression of hexokinase 2 in tumor cells can suppress transcription of the gene encoding IFN-γ, contributing to immune response evasion.
“For example, high expression of hexokinase 2 (HK2) in tumor cells can suppress transcription of the gene encoding IFN-γ, thereby contributing to immune response evasion.271”
From Drug repurposing for cancer therapy (2024) · cites this paper as [271]
In Results, HK2-overexpressing melanoma cells were associated with lower IFN-γ production by infiltrating CD4+ T cells and greater evasion of CD4+ T-cell surveillance. The same section reports an inverse correlation between tumor HK2 and Ifng mRNA, but does not show that HK2 directly suppresses transcription of the IFN-γ gene. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAdministration of blocking antibodies to CTLA4/PD1 can restore glucose metabolism in mouse TILs contributing to tumour eradication.
“administration of blocking antibodies to CTLA4/PD1 can restore glucose metabolism in mouse TILs contributing to tumour eradication [80].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [80]
T regulatory cells (Tregs) are an inhibitory T cell population highly represented at the tumour site and characterized by AMPK-dependent metabolic requirements.
“the induction of T regulatory cells (Tregs), an inhibitory T cell population, highly represented at the tumour site and characterized by AMPK-dependent metabolic requirements [80].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [80]
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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
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 162
- Issue
- 6
- Pages
- 1217-1228
- ISSN
- 0092-8674 (ISSN-L)
- 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
- 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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