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Modulation of EZH2 Expression in T Cells Improves Efficacy of anti-CTLA-4 Therapy

Modulation of EZH2 Expression in T Cells Improves Efficacy of anti-CTLA-4 Therapy

Sangeeta Goswami, Irina Apostolou, Jan Zhang, Jill Skepner, Swetha Anandhan, Xuejun Zhang, Liangwen Xiong, Patrick Trojer, Ana Aparicio, Sumit K Subudhi, James P Allison, Hao Zhao, Padmanee Sharma

J Clin Invest. 2018 Aug 31;128(9):3813-3818.

PMID: 29905573

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42416105	EZH2 human			Price

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