EZH2 inhibitor GSK126 suppresses antitumor immunity by driving production of myeloid-derived suppressor cells

Abstract

Enhancer of zeste homolog (EZH2) is a key epigenetic regulator of gene expression and is frequently overexpressed in various cancer types, suggesting a role in oncogenesis. The therapeutic potential of EZH2 inhibitors is currently being explored, but their effect on antitumor immunity is largely unknown. Here we report that suppressing EZH2 activity using EZH2 inhibitor GSK126 resulted in increased numbers of myeloid-derived suppressor cells (MDSC) and fewer CD4þ and IFNg þCD8þ T cells, which are involved in antitumor immunity. Addition of a neutralizing antibody against the myeloid differentiation antigen GR-1 or gemcitabine/5-fluo-rouracil–depleted MDSCs alleviated MDSC-mediated immu-nosuppression and increased CD4þ and CD8þ T-cell tumor infiltration and GSK126 therapeutic efficacy. Mechanistically, we identified a novel pathway of MDSC production in cancer in which EZH2 inhibition directs myeloid differentiation from primitive hematopoietic progenitor cells. These findings suggest that modulating the tumor immune microenvironment may improve the efficacy of EZH2 inhibitors. Significance: This study uncovers a potential mechanism behind disappointing results of a phase I clinical trial of EZH2 inhibitor GSK126 and identifies a translatable combinational strategy to overcome it.