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. 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

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Free PMC article

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

Sangeeta Goswami et al. J Clin Invest. .
Free PMC article

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.

Conflict of interest statement

Conflict of interest: PS has consulted for Constellation Pharmaceuticals, Jounce Therapeutics, Kite Pharma, Evelo, Astellas Pharma, AstraZeneca, Amgen, GlaxoSmithKline, and Bristol-Myers Squibb. PS serves on the scientific advisory boards for Jounce Therapeutics, Neon, Constellation Pharmaceuticals, and Kite Pharma. PS is a cofounder of Jounce Therapeutics. PT, JS, and IA serve in the translational research division of Constellation Pharmaceuticals.

Figures

Figure 1
Figure 1. 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.
Figure 2
Figure 2. Ipilimumab increases EZH2 expression in T cells.
(A) Unsupervised hierarchical cluster analysis of RNA sequencing data from the peripheral CD4+ T cells of patients with metastatic melanoma before and after 3 doses of ipilimumab therapy (week 7). (B) Matched, paired analysis of EZH2 expression before and after ipilimumab therapy. (C) EZH2 expression in peripheral CD4+ T cells from patients with metastatic prostate cancer at baseline and after 3 doses of ipilimumab therapy. A 2-tailed Student’s t test was used to determine significance; **P < 0.01.
Figure 3
Figure 3. Blocking expression of EZH2 mediated by anti–CTLA-4 using CPI-1205 increases the effectiveness of anti–CTLA-4 therapy.
Tumor growth (A), survival (B), and percentages of intra-tumoral CD4+CD25+FoxP3+ Tregs, CD4+ICOS+T-bet+, and CD8+IFN-γ+ cells (C) in MB49 tumor-bearing mice treated with vehicle, anti–CTLA-4, CPI-1205, or the combination. Tumor growth (D) and percentages of CD4+IFN-γ+ cells and CD8+TNF-α+ cells in the lymph nodes (LN) (E) of MB49 tumor-bearing EZH2fl/+ and FoxP3CreEZH2fl/fl mice treated with anti–CTLA-4 on days 7 and 9. (F) Tumor growth and survival of MB49 tumor-bearing Rag-1−/− mice treated with vehicle or CPI-1205. Data are representative of 3 independent experiments; n = 10 in each group; 1-way ANOVA was used to determine significance between the groups; **P < 0.01.

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