The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction
Open accessAbstract
Aerobic glycolysis regulates T cell function. However, whether and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity in cancer patients remains a question. Here we found that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNAs miR-101 and miR-26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, small hairpin RNA-mediated knockdown of human EZH2 in T cells elicited poor antitumor immunity. EZH2(+)CD8(+) T cells were associated with improved survival in patients. Together, these data unveil a metabolic target and mechanism of cancer immune evasion.
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?
In the citing paper
“short hairpin RNAs (shRNAs) targeting EZH2 compromise the ability of CD8 + CTLs to mount robust immune responses”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Zhao et al., 2016
In the citing paper
“correlating with a positive prognostic impact for tumor infiltration by EHZ2 + CD8 + cells in patients with ovarian cancer”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Zhao et al., 2016
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
Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome
Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pagès, C., Tosolini, M., Camus, M., Berger, A., Wind, P., et al. (2006) · Science · doi:10.1126/science.1129139 · Cited by 6,516
Curiel, T. J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., Evdemon-Hogan, M., Conejo-Garcia, J. R., Zhang, L., Burow, M., et al. (2004) · Nature Medicine · doi:10.1038/nm1093 · Cited by 5,151
Self-citationWherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062
Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing
Cao, R., Wang, L., Wang, H., Xia, L., Erdjument-Bromage, H., Tempst, P., Jones, R. S., & Zhang, Y. (2002) · Science · doi:10.1126/science.1076997 · Cited by 3,775
Self-citationIntratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer
Zhang, L., Conejo-Garcia, J. R., Katsaros, D., Gimotty, P. A., Massobrio, M., Regnani, G., Makrigiannakis, A., Gray, H., Schlienger, K., Liebman, M. N., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa020177 · Cited by 3,397
Time‐Dependent ROC Curves for Censored Survival Data and a Diagnostic Marker
Heagerty, P. J., Lumley, T., & PEPE, M. S. (2000) · Biometrics · doi:10.1111/j.0006-341x.2000.00337.x · Cited by 2,870
The polycomb group protein EZH2 is involved in progression of prostate cancer
Varambally, S., Dhanasekaran, S. M., Zhou, M., Barrette, T. R., Kumar-Sinha, C., Sanda, M. G., Ghosh, D., Pienta, K. J., Sewalt, R. G. A. B., Otte, A. P., et al. (2002) · Nature · doi:10.1038/nature01075 · Cited by 2,717
Self-citationThe Polycomb group protein EZH2 directly controls DNA methylation
Viré, E., Brenner, C., Deplus, R., Blanchon, L., Fraga, M., Didelot, C., Morey, L., Van Eynde, A., Bernard, D., Vanderwinden, J.-M., et al. (2006) · Nature · doi:10.1038/nature04431 · Cited by 2,204
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
Effector Memory T Cells, Early Metastasis, and Survival in Colorectal Cancer
Pagès, F., Berger, A., Camus, M., Sanchez-Cabo, F., Costes, A., Molidor, R., Mlecnik, B., Kirilovsky, A., Nilsson, M., Damotte, D., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa051424 · Cited by 2,135
A human memory T cell subset with stem cell–like properties
Gattinoni, L., Lugli, E., Ji, Y., Pos, Z., Paulos, C. M., Quigley, M. F., Almeida, J. R., Gostick, E., Yu, Z., Carpenito, C., et al. (2011) · Nature Medicine · doi:10.1038/nm.2446 · Cited by 1,974
EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations
McCabe, M. T., Ott, H. M., Ganji, G., Korenchuk, S., Thompson, C., Van Aller, G. S., Liu, Y., Graves, A. P., III, A. D. P., Diaz, E., et al. (2012) · Nature · doi:10.1038/nature11606 · Cited by 1,786
Self-citationAdoptive cell transfer: a clinical path to effective cancer immunotherapy
Rosenberg, S. A., Restifo, N. P., Yang, J. C.-H., Morgan, R. A., & Dudley, M. E. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2355 · Cited by 1,654
Checking the Cox model with cumulative sums of martingale-based residuals
LIN, D. Y., WEI, L. J., & YING, Z. (1993) · Biometrika · doi:10.1093/biomet/80.3.557 · Cited by 1,432
Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity
Curiel, T. J., Wei, S., Dong, H., Alvarez, X., Cheng, P., Mottram, P., Krzysiek, R., Knutson, K. L., Daniel, B., Zimmermann, M. C., et al. (2003) · Nature Medicine · doi:10.1038/nm863 · Cited by 1,314
Self-citationGenomic Loss of microRNA-101 Leads to Overexpression of Histone Methyltransferase EZH2 in Cancer
Varambally, S., Cao, Q., Mani, R. S., Shankar, S., Wang, X., Ateeq, B., Laxman, B., Cao, X., Jing, X., Ramnarayanan, K., et al. (2008) · Science · doi:10.1126/science.1165395 · Cited by 1,064
Self-citationAmsen, D., Blander, J. M., Lee, G. R., Tanigaki, K., Honjo, T., & Flavell, R. A. (2004) · Cell · doi:10.1016/s0092-8674(04)00451-9 · Cited by 910
Tan, J., Yang, X., Zhuang, L., Jiang, X., Chen, W., Lee, P. L., Karuturi, R. K. M., Tan, P. B. O., Liu, E. T., & Yu, Q. (2007) · Genes & Development · doi:10.1101/gad.1524107 · Cited by 895
Kryczek, I., Banerjee, M., Cheng, P. J., Vatan, L., Szeliga, W., Wei, S., Huang, E. H., Finlayson, E. V. A., Simeone, D. M., Welling, T. H., et al. (2009) · Blood · doi:10.1182/blood-2009-03-208249 · Cited by 852
Self-citationT cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment
Crespo, J., Sun, H., Welling, T. H., Tian, Z., & Zou, W. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.12.003 · Cited by 752
Self-citationB7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma
Kryczek, I., Zou, L., Rodriguez, P., Zhu, G., Wei, S., Mottram, P., Brumlik, M., Cheng, P., Curiel, T., Myers, L., et al. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20050930 · Cited by 748
Self-citationAlmeida, J. R., Price, D. A., Papagno, L., Arkoub, Z. A., Sauce, D., Bornstein, E. R., Asher, T. E., Samri, A., Schnuriger, A., Theodorou, I. D., et al. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20070784 · Cited by 725
Zou, W., Machelon, V., L’Herminé, A. C., Borvak, J., Mercier‐Nomé, F., Isaeva, T., Wei, S., Krzysiek, R., Durand–Gasselin, I., Gordon, A. N., et al. (2001) · Nature Medicine · doi:10.1038/nm1201-1339 · Cited by 678
Self-citationTH17 cells in tumour immunity and immunotherapy
Zou, W., & Restifo, N. P. (2010) · Nature reviews. Immunology · doi:10.1038/nri2742 · Cited by 657
Self-citationDecade-Long Safety and Function of Retroviral-Modified Chimeric Antigen Receptor T Cells
Scholler, J., Brady, T., Binder-Scholl, G. K., Hwang, W., Plesa, G., Hege, K. M., Vogel, A. N., Kalos, M. D., Riley, J. L., Deeks, S. G., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003761 · Cited by 653
Miranda, T. B., Cortez, C. C., Yoo, C. B., Liang, G., Abe, M., Kelly, T. K., Márquez, V. E., & Jones, P. A. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0013 · Cited by 609
Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses
Gaucher, D., Therrien, R., Kettaf, N., Angermann, B., Boucher, G., Filali-Mouhim, A., Moser, J. M., Mehta, R. S., Drake, D. R., Castro, E., et al. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20082292 · Cited by 589
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
Precopio, M., Betts, M. R., Parrino, J., Price, D. A., Emma Gostick, D., Ambrozak, D. R., Asher, T. E., Douek, D. C., Harari, A., Pantaleo, G., et al. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20062363 · Cited by 492
Ciofani, M., & Zúñiga‐Pflücker, J. C. (2005) · Nature Immunology · doi:10.1038/ni1234 · Cited by 481
Th17 cells are long lived and retain a stem cell-like molecular signature
Muranski, P., Borman, Z. A., Kerkar, S. P., Klebanoff, C. A., Ji, Y., Sanchez-Perez, L., Sukumar, M., Reger, R. N., Yu, Z., Kern, S. J., et al. (2011) · Immunity · doi:10.1016/j.immuni.2011.09.019 · Cited by 443
Marrack, P., & Kappler, J. (2003) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104554 · Cited by 439
Cui, T. X., Kryczek, I., Zhao, L., Zhao, E., Kuick, R. D., Roh, M. H., Vatan, L., Szeliga, W., Mao, Y., Thomas, D. G., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.08.025 · Cited by 434
Self-citationÖberg, C., Li, J., Pauley, A. M., Wolf, E., Gurney, M. E., & Lendahl, U. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m103992200 · Cited by 412
Kryczek, I., Lin, Y., Nagarsheth, N., Peng, D., Zhao, L., Zhao, E., Vatan, L., Szeliga, W., Dou, Y., Owens, S. R., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.03.010 · Cited by 401
Self-citationYang, K., Shrestha, S., Zeng, H., Karmaus, P. W. F., Neale, G. A. M., Vogel, P., Guertin, D. A., Lamb, R. F., & Chi, H. (2013) · Immunity · doi:10.1016/j.immuni.2013.09.015 · Cited by 397
MYC stimulates EZH2 expression by repression of its negative regulator miR-26a
Sander, S., Bullinger, L., Klapproth, K., Fiedler, K., Kestler, H. A., Barth, T. F. E., Möller, P., Stilgenbauer, S., Pollack, J. R., & Wirth, T. (2008) · Blood · doi:10.1182/blood-2008-03-147645 · Cited by 396
Fiskus, W. C., Wang, Y., Sreekumar, A., Buckley, K. M., Shi, H., Jillella, A., Üstün, C., Rao, R., Fernandez, P., Chen, J., et al. (2009) · Blood · doi:10.1182/blood-2009-03-213496 · Cited by 372
Self-citationWirtz‐Peitz, F., Nishimura, T., & Knoblich, J. A. (2008) · Cell · doi:10.1016/j.cell.2008.07.049 · Cited by 370
Harari, A., Bart, P., Stöhr, W., Tapia, G., Garcia, M., Medjitna-Rais, E., Burnet, S., Cellerai, C., Erlwein, O. W., Barber, T., et al. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20071331 · Cited by 299
Powell, D. J., Dudley, M. E., Robbins, P. F., & Rosenberg, S. A. (2004) · Blood · doi:10.1182/blood-2004-06-2482 · Cited by 295
Tumes, D. J., Onodera, A., Suzuki, A., Shinoda, K., Endo, Y., Iwamura, C., Hosokawa, H., Koseki, H., Tokoyoda, K., Suzuki, Y., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.09.012 · Cited by 291
Human T H 17 Cells Are Long-Lived Effector Memory Cells
Kryczek, I., Zhao, E., Liu, Y., Wang, Y., Vatan, L., Szeliga, W., Moyer, J., Klimczak, A., Lange, A., & Zou, W. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002949 · Cited by 278
Self-citationExpression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells
Kryczek, I., Liu, S., Roh, M. H., Vatan, L., Szeliga, W., Wei, S., Banerjee, M., Mao, Y., Kotarski, J., Wicha, M. S., et al. (2011) · International Journal of Cancer · doi:10.1002/ijc.25967 · Cited by 275
Self-citationThe precursors of memory: models and controversies
Ahmed, R., Bevan, M. J., Reiner, S. L., & Fearon, D. T. (2009) · Nature reviews. Immunology · doi:10.1038/nri2619 · Cited by 207
Role of Deltex-1 as a Transcriptional Regulator Downstream of the Notch Receptor
Yamamoto, N., Yamamoto, S.-I., Inagaki, F. F., Kawaichi, M., Fukamizu, A., Kishi, N., Matsuno, K., Nakamura, K., Weinmaster, G., Okano, H., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105245200 · Cited by 189
A Molecular Basis for the Control of Preimmune Escape Variants by HIV-Specific CD8+ T Cells
Ladell, K., Hashimoto, M., Iglesias, M. C., Wilmann, P. G., McLaren, J. E., Gras, S., Chikata, T., Kuse, N., Fastenackels, S., Emma Gostick, D., et al. (2013) · Immunity · doi:10.1016/j.immuni.2012.11.021 · Cited by 149
Zheng, Y., Zha, Y., Driessens, G., Locke, F. L., & Gajewski, T. F. (2012) · The Journal of Experimental Medicine · doi:10.1084/jem.20120342 · Cited by 106
Tong, Q., He, S., Xie, F., Mochizuki, K., Liu, Y., Mochizuki, I., Meng, L., Sun, H., Zhang, Y., Guo, Y., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302943 · Cited by 67
Self-citationTh17 cells have stem cell-like features and promote long-term immunity
Wei, S., Zhao, E., Kryczek, I., & Zou, W. (2012) · OncoImmunology · doi:10.4161/onci.19440 · Cited by 50
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Zou, W., Wolchok, J. D., & Chen, L. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad7118 · Cited by 2,400
Self-citationChemokines in the cancer microenvironment and their relevance in cancer immunotherapy
Nagarsheth, N., Wicha, M. S., & Zou, W. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.49 · Cited by 2,251
Self-citationPitt, J. M., Marabelle, A., Eggermont, A. M. M., Soria, J., Kroemer, G., & Zitvogel, L. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw168 · Cited by 1,355
Metabolic Instruction of Immunity
Buck, M. D., Sowell, R., Kaech, S. M., & Pearce, E. L. (2017) · Cell · doi:10.1016/j.cell.2017.04.004 · Cited by 1,270
Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion
Leone, R. D., Zhao, L., Englert, J. M., Sun, I.-M., Oh, M.-H., Sun, I.-H., Arwood, M. L., Bettencourt, I. A., Patel, C. H., Wen, J., et al. (2019) · Science · doi:10.1126/science.aav2588 · Cited by 1,169
Self-citation
Metadata
- Authors
- Zhao, E., Maj, T., Kryczek, I., Li, W., Wu, K., Zhao, L., Wei, S., Crespo, J., Wan, S., Vatan, L., Szeliga, W., Shao, I., Wang, Y., Liu, Y., Varambally, S., Chinnaiyan, A. M., Welling, T. H., Marquez, V., Kotarski, J., Wang, H., Wang, Z., Zhang, Y., Liu, R., Wang, G., & Zou, W.
- Affiliations
- University of Michigan (US)
- Medical University of Lublin (PL)
- Wuhan Union Hospital (CN)
- Corresponding author
- Wang, Guobin
- Zou, Weiping
- ORCID
- Venue
- Nature Immunology
- Published
- 2015-11-02
- Volume
- 17
- Issue
- 1
- Pages
- 95-103
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC4684796
- OpenAlex
- W2202401513
- Cited by
- 405
- References
- 50
- Citations by year
- 2026: 19 · 2025: 30 · 2024: 37 · 2023: 35 · 2022: 54 · 2021: 51 · 2020: 42 · 2019: 34 · 2018: 38 · 2017: 35 · 2016: 29 · 2015: 1
- FWCI
- 15.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL127351)
- National Cancer Institute (R01CA092562, CA099985, R01CA123088, R01CA152470, R01CA156685, R01CA172106, CA123088, 5P30 CA 46592, CA156685, R01CA171306, R01CA193136, CA171306, R01CA099985, R01CA190176, P30CA046592)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- tumor immune evasion, EZH2, microRNA, miR-101, miR-26a, glycolysis, glucose restriction, Notch signaling, H3K27me3, Numb, FBXW7, T cell apoptosis, ovarian cancer, antitumor immunity, CD8+ T cells
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Animals, Cell Separation, Female, Flow Cytometry, Fluorescent Antibody Technique, Glycolysis, Humans, Melanoma, Experimental, Mice, Inbred C57BL, Neoplasms, Ovarian Neoplasms, T-Lymphocytes, Transfection, Immunoblotting, Gene Expression Regulation, Neoplastic, Tumor Escape, MicroRNAs, Tissue Array Analysis, Chromatin Immunoprecipitation, Real-Time Polymerase Chain Reaction, Polycomb Repressive Complex 2
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
