Modulation of EZH2 expression in T cells improves efficacy of anti–CTLA-4 therapy
Menée in vitro et à l'aide de modèles murins de mélanome ou de cancer de la vessie ainsi que d'échantillons tumoraux prélevés sur des patients atteints d'un mélanome métastatique ou d'un cancer de la prostate traité par ipilimumab, cette étude met en évidence l'intérêt de cibler l'expression de l'enzyme EZH2 pour améliorer l'efficacité des traitements anti-CTLA-4
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.