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

Academic Article

Abstract

  • © 2016 Nature America, Inc. 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.
  • Published In

  • Nature Immunology  Journal
  • Digital Object Identifier (doi)

    Author List

  • Zhao E; Maj T; Kryczek I; Li W; Wu K; Zhao L; Wei S; Crespo J; Wan S; Vatan L
  • Start Page

  • 95
  • End Page

  • 103
  • Volume

  • 17
  • Issue

  • 1