Cited by 407Cancer Immunotherapy and BiomarkersCancer, Hypoxia, and MetabolismT-cell and B-cell Immunology

Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction

Open access
Zhao, Ende, Maj, Tomasz, Kryczek, Ilona, Li, Wei, Wu, Ke, Zhao, Lili, Wei, Shuang, Crespo, Joel +17 more·2016·Nature Immunology

Abstract

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.

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  • Short hairpin RNAs targeting EZH2 impair the ability of CD8+ cytotoxic T lymphocytes to mount strong immune responses.

    “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 ovarian cancer patients, tumor infiltration by EZH2+CD8+ cells correlates with a positive prognosis.

    “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

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  1. [19]Kryczek I Human TH17 Cells Are Long–Lived Effector Memory Cells Sci. Transl. Med 2011 3 104ra100 PMC3345568 21998407

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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
Venue
Nature Immunology
Published
2015-11-02
Volume
17
Issue
1
Pages
95-103
ISSN
  • 1529-2908 (ISSN-L)
  • 1529-2916
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
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

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