The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index.
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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“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]
Experimental — accuracy not yet measuredIn the citing paper
“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]
In the citing paper
“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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Cites
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Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590
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Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review
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Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal
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Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia
Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., Chew, A., Gonzalez, V. E., Zheng, Z., Lacey, S. F., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1407222 · Cited by 5,413
Nivolumab plus Ipilimumab in Advanced Melanoma
Wolchok, J. D., Kluger, H., Callahan, M. K., Postow, M. A., Rizvi, N. A., Lesokhin, A. M., Segal, N. H., Ariyan, C. E., Gordon, R.-A., Reed, K., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1302369 · Cited by 4,230
Wherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062 · cited 1×
“T cells displaying such properties are commonly referred to as ‘‘functionally exhausted’’ (Wherry, 2011).”
BackgroundCancer immunotherapy comes of age
Mellman, I., Coukos, G., & Dranoff, G. (2011) · Nature · doi:10.1038/nature10673 · Cited by 3,893
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233
Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis
Chang, C.-H., Curtis, J. D., Maggi, L. B., Faubert, B., Villarino, A. V., O’Sullivan, D., Huang, S. C.-C., van der Windt, G. J. W., Blagih, J., Qiu, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.05.016 · Cited by 2,204
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The Warburg Effect: How Does it Benefit Cancer Cells?
Liberti, M. V., & Locasale, J. W. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.12.001 · Cited by 5,150
Self-citationMechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy
Topalian, S. L., Taube, J. M., Anders, R. A., & Pardoll, D. M. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.36 · Cited by 2,733
Zou, W., Wolchok, J. D., & Chen, L. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad7118 · Cited by 2,400
Understanding the Intersections between Metabolism and Cancer Biology
Heiden, M. G. V., & DeBerardinis, R. J. (2017) · Cell · doi:10.1016/j.cell.2016.12.039 · Cited by 2,369
Miller, B. C., Sen, D. R., Al Abosy, R., Bi, K., Virkud, Y. V., LaFleur, M. W., Yates, K. B., Lako, A., Felt, K., Naik, G. S., et al. (2019) · Nature Immunology · doi:10.1038/s41590-019-0312-6 · Cited by 2,087
Metadata
- 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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