Alteration of the tumor microenvironment by pharmacological inhibition of EZH2 in hepatocellular carcinoma

Enhancer of zeste homolog 2 (EZH2), a core component of polycomb repressive component 2 is overexpressed in a variety of cancers and recognized as a therapeutic target molecule. However, EZH2 possesses immunomodulatory functions in the tumor microenvironment (TME). The impact of EZH2 on TME of hepatocellular carcinoma (HCC) using immunocompetent mouse model was evaluated in the present study. UNC1999, an EZH2 inhibitor, impaired growth of the murine HCC cells (H22 cells) and induced apoptosis in a dose-dependent manner. Although UNC1999 significantly inhibited the growth of H22 cells-derived and Hepa1-6 cells-derived tumors in nonobese diabetic/severe combined immunodeficiency mice, its antitumor effect was diminished in allogenic BALB/c and C57BL/6 mice. Flow cytometric analyses of TME cells in BALB/c mice demonstrated a significant decrease in the number of interferon‑γ+ CD8+ T cells and regulatory T cells and a significant increase in the number of myeloid-derived suppressor cells (MDSCs). Administration of Gr-1 neutralizing antibody concomitant with UNC1999 restored antitumor effect accompanied by an increase in the number of CD8+ T cells followed by a decrease in the number of MDSCs. Chemokine antibody array demonstrated an enhanced expression of chemokines responsible for MDSCs recruitment such as C5a, CCL8, and CCL9. In conclusion, the study results demonstrated that EZH2 inhibitor contributed to attenuation of tumor immunity caused by TME arrangement. Combination therapy with EZH2 inhibitors and agents that reduce MDSCs might represent a novel therapeutic strategy for HCC.

 

Comments：

The present study investigated the impact of EZH2 inhibition on the tumor microenvironment (TME) of hepatocellular carcinoma (HCC) using an immunocompetent mouse model. The study found that UNC1999, an EZH2 inhibitor, inhibited the growth of H22 cells in a dose-dependent manner and induced apoptosis. However, the antitumor effect of UNC1999 was diminished in allogenic BALB/c and C57BL/6 mice.

Flow cytometric analysis of TME cells in BALB/c mice showed that UNC1999 decreased the number of interferon-γ+ CD8+ T cells and regulatory T cells and increased the number of myeloid-derived suppressor cells (MDSCs). Administration of Gr-1 neutralizing antibody concomitant with UNC1999 restored antitumor effect, accompanied by an increase in the number of CD8+ T cells and a decrease in the number of MDSCs. Chemokine antibody array demonstrated an enhanced expression of chemokines responsible for MDSCs recruitment such as C5a, CCL8, and CCL9.

The study suggests that EZH2 inhibition contributes to the attenuation of tumor immunity caused by TME arrangement. Combination therapy with EZH2 inhibitors and agents that reduce MDSCs might represent a novel therapeutic strategy for HCC.

Related Products

Cat.No.	Product Name	Information
S7165	UNC1999	UNC1999 is a potent, orally bioavailable and selective inhibitor of EZH2 and EZH1 with IC50 of 2 nM and 45 nM in cell-free assays, respectively, showing >1000-fold selectivity over a broad range of epigenetic and non-epigenetic targets. UNC1999 is a potent autophagy inducer. UNC1999 specifically suppresses H3K27me3/2 and induces a range of anti-leukemia effects including anti-proliferation, differentiation, and apoptosis.

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Apoptosis related Histone Methyltransferase Autophagy EZH1/2