Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy

J Clin Invest. 2018 Aug 31;128(9):3813-3818. doi: 10.1172/JCI99760. Epub 2018 Jul 30.


Enhancer of zeste homolog 2-mediated (EZH2-mediated) epigenetic regulation of T cell differentiation and Treg function has been described previously; however, the role of EZH2 in T cell-mediated antitumor immunity, especially in the context of immune checkpoint therapy, is not understood. Here, we showed that genetic depletion of EZH2 in Tregs (FoxP3creEZH2fl/fl mice) leads to robust antitumor immunity. In addition, pharmacological inhibition of EZH2 in human T cells using CPI-1205 elicited phenotypic and functional alterations of the Tregs and enhanced cytotoxic activity of Teffs. We observed that ipilimumab (anti-CTLA-4) increased EZH2 expression in peripheral T cells from treated patients. We hypothesized that inhibition of EZH2 expression in T cells would increase the effectiveness of anti-CTLA-4 therapy, which we tested in murine models. Collectively, our data demonstrated that modulating EZH2 expression in T cells can improve antitumor responses elicited by anti-CTLA-4 therapy, which provides a strong rationale for a combination trial of CPI-1205 plus ipilimumab.

Keywords: Epigenetics; Immunology; Immunotherapy; Oncology; T cells.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / administration & dosage
  • Antineoplastic Agents, Immunological / therapeutic use*
  • CTLA-4 Antigen / antagonists & inhibitors*
  • Cell Line, Tumor
  • Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors*
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Indoles / administration & dosage
  • Indoles / pharmacology
  • Ipilimumab / therapeutic use*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms, Experimental / enzymology
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / therapy
  • Piperidines / administration & dosage
  • Piperidines / pharmacology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*


  • Antineoplastic Agents, Immunological
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • Enzyme Inhibitors
  • Indoles
  • Ipilimumab
  • Piperidines
  • (R)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse