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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Immunological / administration & dosage
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Antineoplastic Agents, Immunological / therapeutic use*
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CTLA-4 Antigen / antagonists & inhibitors*
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Cell Line, Tumor
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Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors*
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Enhancer of Zeste Homolog 2 Protein / metabolism
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Enzyme Inhibitors / pharmacology
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Humans
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Indoles / administration & dosage
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Indoles / pharmacology
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Ipilimumab / therapeutic use*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Neoplasms, Experimental / enzymology
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Neoplasms, Experimental / immunology
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Neoplasms, Experimental / therapy
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Piperidines / administration & dosage
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Piperidines / pharmacology
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology*
Substances
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Antineoplastic Agents, Immunological
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CTLA-4 Antigen
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CTLA4 protein, human
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Ctla4 protein, mouse
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Enzyme Inhibitors
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Indoles
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Ipilimumab
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Piperidines
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(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
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein
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Ezh2 protein, mouse