Alteration of the tumor microenvironment by pharmacological inhibition of EZH2 in hepatocellular carcinoma.
Alteration of the tumor microenvironment by pharmacological inhibition of EZH2 in hepatocellular carcinoma.
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DOI：
10.1016/j.intimp.2023.110068
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发表时间：
2023-03
影响因子：
5.6
通讯作者：
Na Qiang;Junjie Ao;Masato Nakamura;T. Chiba;Yuko Kusakabe;Tatsuya Kaneko;A. Kurosugi;Tadayoshi Kogu
中科院分区：
文献类型：
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作者：
Na Qiang;Junjie Ao;Masato Nakamura;T. Chiba;Yuko Kusakabe;Tatsuya Kaneko;A. Kurosugi;Tadayoshi Kogu
Zeste增强子同源物2（EZH 2）是polycomb阻遏组分2的核心组分，在多种癌症中过表达，并被认为是治疗靶分子。然而，EZH 2在肿瘤微环境（TME）中具有免疫调节功能。本研究利用免疫活性小鼠模型评价EZH 2对肝细胞癌（HCC）TME的影响。EZH 2抑制剂UNC 1999以剂量依赖性方式损害小鼠HCC细胞（H22细胞）的生长并诱导细胞凋亡。尽管UNC 1999在非肥胖糖尿病/严重联合免疫缺陷小鼠中显著抑制H22细胞衍生和Hepa 1 -6细胞衍生肿瘤的生长，但其在同种异体BALB/c和C57 BL/6小鼠中的抗肿瘤作用减弱。BALB/c小鼠TME细胞的流式细胞术分析表明，干扰素-γ+ CD 8 +T细胞和调节性T细胞的数量显著减少，髓源性抑制细胞（MDSC）的数量显著增加。Gr-1中和抗体与UNC 1999联合给药恢复了抗肿瘤作用，伴随着CD 8 +T细胞数量的增加，随后是MDSC数量的减少。趋化因子抗体阵列显示负责MDSC募集的趋化因子如C5 a、CCL 8和CCL 9的表达增强。总之，研究结果表明EZH 2抑制剂有助于减弱由TME排列引起的肿瘤免疫。EZH 2抑制剂和减少MDSC的药物的联合治疗可能代表HCC的新治疗策略。
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.