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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590
Cerami, E., Gao, J., Dogrusoz, U., Gross, B. E., Sumer, S. O., Aksoy, B. A., Jacobsen, A., Byrne, C. J., Heuer, M. L., Larsson, E., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0095 · Cited by 17,455
Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review
Wanchoo, R., Karam, S., Uppal, N. N., Barta, V. S., Deray, G., Devoe, C., Launay‐Vacher, V., Jhaveri, K. D., & on behalf of Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors (2017) · American Journal of Nephrology · doi:10.1159/000455014 · Cited by 15,320
Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal
Gao, J., Aksoy, B. A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S. O., Sun, Y., Jacobsen, A., Sinha, R., Larsson, E., et al. (2013) · Science Signaling · doi:10.1126/scisignal.2004088 · Cited by 15,160
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
Smith-Garvin, J. E., Koretzky, G. A., & Jordan, M. S. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132706 · Cited by 2,144
The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation
Wang, R., Dillon, C. P., Shi, L. Z., Milasta, S., Carter, R., Finkelstein, D., McCormick, L. L., Fitzgerald, P., Chi, H., Munger, J., et al. (2011) · Immunity · doi:10.1016/j.immuni.2011.09.021 · Cited by 2,140 · cited 6×
“Additionally, treating TH1 CD4+ T cells with PKM2activatorDASS,whichwill decrease intracellularPEP levels (data not shown) (Anastasiou et al., 2012), similarly suppressed the production of IFNg and CD40L (Figure S5C).”
BackgroundResultInfluentialMichalek, R. D., Gerriets, V. A., Jacobs, S. R., Macintyre, A. N., MacIver, N. J., Mason, E. F., Sullivan, S. A., Nichols, A. G., & Rathmell, J. C. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003613 · Cited by 2,091
Self-citationOncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.058 · Cited by 2,043
Self-citationCTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms
Parry, R. V., Chemnitz, J. M., Frauwirth, K. A., Lanfranco, A. R., Braunstein, I., Kobayashi, S. V., Linsley, P. S., Thompson, C. B., & Riley, J. L. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.21.9543-9553.2005 · Cited by 1,931
Schwartz, R. H. (2003) · Annual Review of Immunology · doi:10.1146/annurev.immunol.21.120601.141110 · Cited by 1,487
The CD28 Signaling Pathway Regulates Glucose Metabolism
Frauwirth, K. A., Riley, J. L., Harris, M. H., Parry, R. V., Rathmell, J. C., Plas, D. R., Elstrom, R. L., June, C. H., & Thompson, C. B. (2002) · Immunity · doi:10.1016/s1074-7613(02)00323-0 · Cited by 1,475 · cited 1×
“Metabolic flexibility allows activated T cells to adapt to changes in glucose availability by utilizing alternative substrates 1226 Cell 162, 1217–1228, September 10, 2015 ª2015 Elsevier Inc. for energy production (Blagih et al., 2015; Frauwirth et al., 2002).”
BackgroundSelf-citationFueling Immunity: Insights into Metabolism and Lymphocyte Function
Pearce, E. L., Poffenberger, M. C., Chang, C.-H., & Jones, R. G. (2013) · Science · doi:10.1126/science.1242454 · Cited by 1,363
Metabolic Regulation of T Lymphocytes
MacIver, N. J., Michalek, R. D., & Rathmell, J. C. (2013) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032712-095956 · Cited by 1,244
Self-citationBrafV600E cooperates with Pten loss to induce metastatic melanoma
Dankort, D., Curley, D. P., Cartlidge, R. A., Nelson, B., Karnezis, A. N., Damsky Jr, W. E., You, M. J., DePinho, R. A., McMahon, M., & Bosenberg, M. (2009) · Nature Genetics · doi:10.1038/ng.356 · Cited by 1,189
Self-citationMacintyre, A. N., Gerriets, V. A., Nichols, A., Michalek, R. D., Rudolph, M. C., Deoliveira, D., Anderson, S. M., Abel, E. D., Chen, B. J., Hale, L. P., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.05.004 · Cited by 1,169
Self-citationMoran, A. E., Holzapfel, K. L., Xing, Y., Cunningham, N. R., Maltzman, J. S., Punt, J. A., & Hogquist, K. A. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20110308 · Cited by 1,050
Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis
Anastasiou, D., Yu, Y., Israelsen, W. J., Jiang, J.-K., Boxer, M. B., Hong, B. S., Tempel, W., Dimov, S., Shen, M., Jha, A., et al. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.1060 · Cited by 816
T-helper-1-cell cytokines drive cancer into senescence
Braumüller, H., Wieder, T., Brenner, E., Aßmann, S., Hahn, M., Alkhaled, M., Schilbach, K., Essmann, F., Kneilling, M., Griessinger, C., et al. (2013) · Nature · doi:10.1038/nature11824 · Cited by 720
The Energy Sensor AMPK Regulates T Cell Metabolic Adaptation and Effector Responses In Vivo
Blagih, J., Coulombe, F., Vincent, E. E., Dupuy, F., Galicia-Vázquez, G., Yurchenko, E., Raissi, T. C., van der Windt, G. J. W., Viollet, B., Pearce, E. L., et al. (2015) · Immunity · doi:10.1016/j.immuni.2014.12.030 · Cited by 679
Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen
Doedens, A. L., Phan, A. T., Stradner, M. H., Fujimoto, J. K., Nguyen, J. V., Yang, E., Johnson, R. S., & Goldrath, A. W. (2013) · Nature Immunology · doi:10.1038/ni.2714 · Cited by 660 · cited 2×
“Additionally, rewiring the metabolic activity of TILs, as demonstrated herein and elsewhere (Doedens et al., 2013), could pose a new strategy for enhancing the potency and durability of ACT.”
BackgroundInfluentialEvidence for an Alternative Glycolytic Pathway in Rapidly Proliferating Cells
Heiden, M. G. V., Locasale, J. W., Swanson, K. D., Sharfi, H., Heffron, G. J., Amador‐Noguez, D., Christofk, H. R., Wagner, G., Rabinowitz, J. D., Asara, J. M., et al. (2010) · Science · doi:10.1126/science.1188015 · Cited by 648
Self-citationFinlay, D. K., Rosenzweig, E., Sinclair, L. V., Feijoo-Carnero, C., Hukelmann, J. L., Rolf, J., Panteleyev, A. A., Okkenhaug, K., & Cantrell, D. A. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20112607 · Cited by 596
Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch
Gubser, P. M., Bantug, G. R., Razik, L., Fischer, M., Dimeloe, S., Höenger, G., Müller-Durovic, B., Jauch, A., & Hess, C. (2013) · Nature Immunology · doi:10.1038/ni.2687 · Cited by 500
Egr-2 and Egr-3 are negative regulators of T cell activation
Safford, M., Collins, S. L., Lutz, M. A., Allen, A. N., Huang, C.-T., Kowalski, J., Blackford, A. L., Horton, M. R., Drake, C. G., Schwartz, R. H., et al. (2005) · Nature Immunology · doi:10.1038/ni1193 · Cited by 446
Oncometabolites: linking altered metabolism with cancer
Yang, M. H., Soga, T., & Pollard, P. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67228 · Cited by 441
Ion channels and transporters in lymphocyte function and immunity
Feske, S., Skolnik, E. Y., & Prakriya, M. (2012) · Nature Reviews Immunology · doi:10.1038/nri3233 · Cited by 441
Self-citationStaron, M. M., Gray, S. M., Marshall, H. D., Parish, I. A., Chen, J. H., Perry, C. J., Cui, G., Li, M. O., & Kaech, S. M. (2014) · Immunity · doi:10.1016/j.immuni.2014.10.013 · Cited by 398
Self-citationCham, C. M., Driessens, G., O'Keefe, J. P., & Gajewski, T. F. (2008) · European Journal of Immunology · doi:10.1002/eji.200838289 · Cited by 388
Immune microenvironments in solid tumors: new targets for therapyPreprint
Shiao, S. L., Ganesan, A.-P., Rugo, H. S., & Coussens, L. M. (2011) · Genes & Development · doi:10.1101/gad.169029.111 · Cited by 331
Anergic T Cells Are Metabolically Anergic
Zheng, Y., Delgoffe, G. M., Meyer, C. F., Chan, W., & Powell, J. D. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803510 · Cited by 289
Anti–CTLA-4 Antibody Therapy: Immune Monitoring During Clinical Development of a Novel Immunotherapy
Callahan, M. K., Wolchok, J. D., & Allison, J. P. (2010) · Seminars in Oncology · doi:10.1053/j.seminoncol.2010.09.001 · Cited by 248
THE INTERSTITIAL FLUID OF SOLID TUMORS.
Gullino, P. M., Clark, S. H., & Grantham, F. H. (1964) · PubMed · Cited by 238
Pentcheva‐Hoang, T., Corse, E., & Allison, J. P. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2009.00763.x · Cited by 203
The three main stumbling blocks for anticancer T cells
Baitsch, L., Marraco, S. A. F., Legat, A., Meyer, C., & Speiser, D. E. (2012) · Trends in Immunology · doi:10.1016/j.it.2012.02.006 · Cited by 148
Immune-based antitumor effects of BRAF inhibitors rely on signaling by CD40L and IFNγ
Ho, P.-C., Meeth, K. M., Tsui, Y.-C., Srivastava, B., Bosenberg, M. W., & Kaech, S. M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-3461 · Cited by 126
Self-citationQin, F., Siwik, D. A., Lancel, S., Zhang, J., Kuster, G. M., Luptak, I., Wang, L., Tong, X., Kang, Y. J., Cohen, R. A., et al. (2013) · Journal of the American Heart Association · doi:10.1161/jaha.113.000184 · Cited by 122
Sharov, V. S., Dremina, E. S., Galeva, N. A., Williams, T. D., & Schöneich, C. (2006) · Biochemical Journal · doi:10.1042/bj20051214 · Cited by 121
Early T Cell Signalling Is Reversibly Altered in PD-1+ T Lymphocytes Infiltrating Human Tumors
Renault, S., Fouquet, S., Chapon, M., Salmon, H., Régnier, F., Labroquère, K., Badoual, C., Damotte, D., Validire, P., Maubec, E., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017621 · Cited by 92
Borge, P. D., & Wolf, B. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209521200 · Cited by 43
Srinivasan, M., & Frauwirth, K. A. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.6.3734 · Cited by 42
Cytoplasmic receptor-interacting protein 140 (RIP140) interacts with perilipin to regulate lipolysis
Ho, P., Chuang, Y.-S., Hung, C.-H., & Wei, L. (2011) · Cellular Signalling · doi:10.1016/j.cellsig.2011.03.023 · Cited by 30
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
