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

• Published in: Nature immunology Vol. 17; no. 1; pp. 95 - 103
• Main Authors: Zhao, Ende, Maj, Tomasz, Kryczek, Ilona, Li, Wei, Wu, Ke, Zhao, Lili, Wei, Shuang, Crespo, Joel, Wan, Shanshan, Vatan, Linda, Szeliga, Wojciech, Shao, Irene, Wang, Yin, Liu, Yan, Varambally, Sooryanarayana, Chinnaiyan, Arul M, Welling, Theodore H, Marquez, Victor, Kotarski, Jan, Wang, Hongbo, Wang, Zehua, Zhang, Yi, Liu, Rebecca, Wang, Guobin, Zou, Weiping
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2016; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/21; 13/31; 13/44; 13/51; 13/89; 13/95; 631/250/1619/554/1834/1269; 631/250/2502/2170; 631/250/580/1884; 64/60; 82/51; 82/80; 96/106; 96/109; Animals; Biomedicine; Cell metabolism; Cell Separation; Chromatin Immunoprecipitation; Development and progression; Enhancer of Zeste Homolog 2 Protein; Female; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic - immunology; Genetic aspects; Glycolysis; Humans; Immunoblotting; Immunology; Infectious Diseases; Melanoma, Experimental - immunology; Mice, Inbred C57BL; MicroRNA; MicroRNAs; Neoplasms - immunology; Ovarian cancer; Ovarian Neoplasms - immunology; Polycomb Repressive Complex 2 - immunology; Properties; Real-Time Polymerase Chain Reaction; T cells; T-Lymphocytes - immunology; Tissue Array Analysis; Transfection; Tumor Escape - immunology
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3313

Glucose availability is limiting in tumor environments. Zou and colleagues show that reduced glycolytic metabolism in T cells within tumors suppresses expression of the methyltransferase EZH2, which limits production of antitumor effector molecules and enhances T cell apoptosis. 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.