Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction (TUM9P.1007)

Aerobic glycolysis regulates T cell function. However, if and how primary cancer alters effector T cell glycolytic metabolism and affects tumor immunity remains a question in cancer patients. Here we report that ovarian cancer imposes glucose restriction on effector T cells, dampens their function via maintaining high expression of microRNA101 and microRNA26a, which subsequently constrains EZH2 expression. EZH2 activates the Notch pathway by suppressing Notch repressors via H3K27me3, and consequently stimulates T cell polyfunctional cytokine expression and promotes their survival via Bcl-2 signaling. Moreover, EZH2-/- T cells elicit poor anti-tumor immunity and EZH2+CD8+ T cells are associated with improved long-term cancer patient survival. Together, our data unveil a novel metabolic target and mechanism of cancer immune evasion.