Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy
Sangeeta Goswami 1, Irina Apostolou 2, Jan Zhang 1, Jill Skepner 2, Swetha Anandhan 1, Xuejun Zhang 3, Liangwen Xiong 1, Patrick Trojer 2, Ana Aparicio 1, Sumit K Subudhi 1, James P Allison 3 4, Hao Zhao 3, Padmanee Sharma 1 3 4

Enhancer of zeste homolog 2-mediated (EZH2-mediated) epigenetic regulating T cell differentiation and Treg function continues to be described formerly however, the function of EZH2 in T cell-mediated antitumor immunity, especially poor immune checkpoint therapy, isn’t understood. Here, we demonstrated that genetic depletion of EZH2 in Tregs (FoxP3creEZH2fl/fl rodents) results in robust antitumor immunity. Additionally, medicinal inhibition of EZH2 in human T cells using CPI-1205 elicited phenotypic and functional alterations from the Tregs that has been enhanced cytotoxic activity of Teffs. We observed that ipilimumab (anti-CTLA-4) elevated EZH2 expression in peripheral T cells from treated patients. We hypothesized that inhibition of EZH2 expression in T cells would increase the potency of anti-CTLA-4 therapy, which we tested in murine models. With each other, our data shown that modulating EZH2 expression in T cells can improve antitumor responses elicited by anti-CTLA-4 therapy, which supplies a powerful rationale for any combination trial of CPI-1205 plus ipilimumab.