Modulation of EZH2 expression in T cells improves efficacy of anti–CTLA-4 therapy
Sangeeta Goswami, … , Hao Zhao, Padmanee Sharma
Sangeeta Goswami, … , Hao Zhao, Padmanee Sharma
Published June 15, 2018
Citation Information: J Clin Invest. 2018;128(9):3813-3818. https://doi.org/10.1172/JCI99760.
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Modulation of EZH2 expression in T cells improves efficacy of anti–CTLA-4 therapy

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.

Authors

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

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Figure 1

EZH2 inhibition by CPI-1205 enhances T cell–mediated antitumor immunity.

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EZH2 inhibition by CPI-1205 enhances T cell–mediated antitumor immunity....
Tumor growth (A) and percentages of intratumoral CD8+IFN-γ+ cells, CD8+GzB+ cells, and CD8+TNF-α+ (B) and FoxP3+IFN-γ+ cells (C) in MB49 tumor-bearing EZH2fl/+ (n = 10) and FoxP3CreEZH2fl/fl (n = 10) mice. (D) Differentiated human iTregs with or without CPI-1205 were cultured with CellTrace Violet–labeled Teffs for 72 hours at various ratios. Data are presented as CellTrace Violet+ proliferating Teffs at different concentrations of CPI-1205. (E) Preactivated human CD4+ and CD8+ T cells (with or without CPI-1205) were cultured with CellTrace Violet–labeled Nalm-6 target cells along with blinatumomab. Data are presented as percentages of Annexin+ 7AAD+ cells at various ratios of effector/target cells. Data are representative of 3 independent experiments. A 2-tailed Student’s t test was used to determine significance; **P < 0.01.