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Nat Immunol. 2016 Jan;17(1):95-103. doi: 10.1038/ni.3313. Epub 2015 Nov 2.

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

Author information

1
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
2
Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
3
Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
4
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
5
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
6
Chemical Biology Laboratory, Center for Cancer Research, NCI-Frederick, Frederick, Maryland, USA.
7
The First Department of Gynecologic Oncology and Gynecology, Medical University of Lublin, Lublin, Poland.
8
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
9
Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
10
Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Arbor, Michigan, USA.
11
Graduate Programs in Immunology and Cancer Biology, University of Michigan, Ann Arbor, Michigan, USA.
12
Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.

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.

PMID:
26523864
PMCID:
PMC4684796
DOI:
10.1038/ni.3313
[Indexed for MEDLINE]
Free PMC Article

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