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

Nat Immunol. 2016 Jan;17(1):95-103. doi: 10.1038/ni.3313. Epub 2015 Nov 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Separation
  • Chromatin Immunoprecipitation
  • Enhancer of Zeste Homolog 2 Protein
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic / immunology*
  • Glycolysis
  • Humans
  • Immunoblotting
  • Melanoma, Experimental / immunology
  • Mice, Inbred C57BL
  • MicroRNAs*
  • Neoplasms / immunology*
  • Ovarian Neoplasms / immunology
  • Polycomb Repressive Complex 2 / immunology*
  • Real-Time Polymerase Chain Reaction
  • T-Lymphocytes / immunology*
  • Tissue Array Analysis
  • Transfection
  • Tumor Escape / immunology*


  • MicroRNAs
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2