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 CD4 þ and IFNg þ CD8 þ T cells, which are involved in antitumor immunity. Addition of a neutralizing antibody against the myeloid differentiation antigen GR-1 or gemcitabine/5-fluorouracil-depleted MDSCs alleviated MDSC-mediated immu-nosuppression and increased CD4 þ and CD8 þ 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.

The Promise for Histone Methyltransferase Inhibitors for Epigenetic Therapy in Clinical Oncology: A Narrative Review

“…These results were further confirmed in a study demonstrating that genetic depletion of EZH2 in T reg cells or EZH2 catalytic inhibition using CPI-1205 elicited phenotypic and functional alterations to T reg cells, along with enhanced activation of effector T cells leading to robust antitumor immunity [215]. However, EZH2 inhibition has also been associated with reduced long-term survival of effector T cells [216,217], along with induction of immunosuppressive myeloid-derived suppressor cells [218], highlighting the need for further evaluation of its diverse role in mediating immune cell function. Collectively, EZH2-mediated epigenetic programs are essential for the lineage commitment as well as the functional immune suppressive activity of T reg cells, along with tumor escape from immune surveillance via downregulation of the antigen presentation pathway, providing a rationale for exploring combination therapies of EZH2 inhibitors with immune checkpoint inhibitors.…”

Depletion of nuclear pore protein NUP210 suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response

“…Treating with an EZH2 inhibitor could adversely affect patient outcome through activation of mechanosensitive genes essential for cell migration and metastasis. In line with this speculation, GSK126 treatment has been shown to exhibit adverse effects via inhibiting anti-tumor immunity 92 and promoting inflammation 93 in pre-clinical models of cancer.…”

EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications

“…Dozens of chemotherapeutic agents have been developed to target the EZH2 enzymatic SET domain for therapeutics; yet, for most of these drugs, satisfactory effectiveness was only seen in B cell lymphoma cell lines or xenografts with EZH2 gain-of-function mutations. Although several compounds of EZH2-SET inhibitors have entered into clinical trials, some have already failed in phase I at least partly due to the negative mediation of anti-tumor immunity [161]. Development of EZH1/2 inhibitors and EED inhibitors represents a big leap, as these agents effectively overcome chemo-resistance of EZH2-SET inhibitors GSK126 and EPZ-6438 in DLBCL [145].…”