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

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 s...

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Bibliographic Details
Published in:The Journal of clinical investigation 2018-09, Vol.128 (9), p.3813-3818
Main Authors: Goswami, Sangeeta, Apostolou, Irina, Zhang, Jan, Skepner, Jill, Anandhan, Swetha, Zhang, Xuejun, Xiong, Liangwen, Trojer, Patrick, Aparicio, Ana, Subudhi, Sumit K, Allison, James P, Zhao, Hao, Sharma, Padmanee
Format: Article
Language:English
Subjects:
Animal models
Antitumor activity
Biomedical research
Cancer
Cell-mediated immunity
Chemokines
Concise Communication
CTLA-4 protein
Cytokines
Cytotoxicity
Epigenetics
Gene expression
Genetic aspects
Health aspects
Immune checkpoint
Immunotherapy
Innovations
Lymphocytes
Lymphocytes T
Medical research
Monoclonal antibodies
Proteins
T cells
Transcription factors
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI99760