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

E Zhao, T Maj, I Kryczek, W Li, K Wu, L Zhao, S Wei… - Nature …, 2016 - nature.com
E Zhao, T Maj, I Kryczek, W Li, K Wu, L Zhao, S Wei, J Crespo, S Wan, L Vatan, W Szeliga…
Nature immunology, 2016nature.com
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 …
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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