%0 Journal Article
%T Modulation of EZH2 expression in T cells improves efficacy of anti每CTLA-4 therapy
%A Ana Aparicio
%A Hao Zhao
%A Irina Apostolou
%A James P. Allison
%A Jan Zhang
%A Jill Skepner
%A Liangwen Xiong
%A Padmanee Sharma
%A Patrick Trojer
%A Sangeeta Goswami
%A Sumit K. Subudhi
%A Swetha Anhan
%A Xuejun Zhang
%J The Journal of Clinical Investigation
%D 2018
%R 10.1172/JCI99760
%X Enhancer of zeste homolog 2每mediated (EZH2-mediated) epigenetic regulation of T cell differentiation and Treg function has been described previously; however, the role of EZH2 in T cell每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每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每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每CTLA-4 therapy, which provides a strong rationale for a combination trial of CPI-1205 plus ipilimumab
%U https://www.jci.org/articles/view/99760