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

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

Author information

1
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
2
Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
3
Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
4
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Abstract

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

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