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

Aerobic glycolysis regulates T cell function. However, if and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity remains a question in cancer patients. Here we report that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNA101 and microRNA26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors, Numb and Fbxw7, via H3K27me3, and consequently stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, human shRNA-knockdown-EZH2-deficient T cells elicited poor anti-tumor immunity. EZH2(+)CD8(+) T cells were associated with improved cancer patient survival. Together, the data unveil a novel metabolic target and mechanism of cancer immune evasion.