title: Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction.
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.
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.|Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ende
authors.initials: E
authors.lastname: Zhao
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Maj
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kryczek
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.|Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.|Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Crespo
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wan
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Vatan
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Szeliga
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Shao
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.|Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
authors.affiliation: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Theodore H
authors.initials: TH
authors.lastname: Welling
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, NCI-Frederick, Frederick, Maryland, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Marquez
authors.affiliation: The First Department of Gynecologic Oncology and Gynecology, Medical University of Lublin, Lublin, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Kotarski
authors.affiliation: Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zehua
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Arbor, Michigan, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Guobin
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.|Graduate Programs in Immunology and Cancer Biology, University of Michigan, Ann Arbor, Michigan, USA.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
mesh_terms: D000818:Animals; D002469:Cell Separation; D047369:Chromatin Immunoprecipitation; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D006019:Glycolysis; D006801:Humans; D015151:Immunoblotting; D008546:Melanoma, Experimental / Q000276:immunology; D008810:Mice, Inbred C57BL; D035683:MicroRNAs; D009369:Neoplasms / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000276:immunology; D063151:Polycomb Repressive Complex 2 / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D046888:Tissue Array Analysis; D014162:Transfection; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D035683:MicroRNAs; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2