通过药物抑制EZH2对肝细胞癌肿瘤微环境进行改变。
Alteration of the tumor microenvironment by pharmacological inhibition of EZH2 in hepatocellular carcinoma.
发表日期：2023 Mar 29
作者：
Na Qiang, Junjie Ao, Masato Nakamura, Tetsuhiro Chiba, Yuko Kusakabe, Tatsuya Kaneko, Akane Kurosugi, Tadayoshi Kogure, Yaojia Ma, Jiaqi Zhang, Keita Ogawa, Motoyasu Kan, Terunao Iwanaga, Takafumi Sakuma, Kengo Kanayama, Hiroaki Kanzaki, Ryuta Kojima, Ryo Nakagawa, Takayuki Kondo, Shingo Nakamoto, Ryosuke Muroyama, Jun Kato, Naoya Mimura, Anqi Ma, Jian Jin, Naoya Kato
来源：
DIABETES & METABOLISM
摘要：
Enhancer of zeste homolog 2 (EZH2)是多聚体抑制复合体2的核心组成部分，在多种癌症中过度表达，并被认为是治疗靶标分子。然而，EZH2在肿瘤微环境（TME）中具有免疫调节功能。本研究评估了EZH2对肝细胞癌（HCC）TME的影响，采用免疫能力小鼠模型。EZH2抑制剂UNC1999能够按剂量依赖性破坏小鼠HCC细胞（H22细胞）的生长并诱导凋亡。虽然UNC1999显著抑制H22和Hepa1-6细胞来源的肿瘤在非肥胖型糖尿病/严重联合免疫缺陷小鼠中的生长，但在同种异体BALB/c和C57BL/6小鼠中，其抗肿瘤效果减弱。BALB/c小鼠TME细胞的流式细胞分析表明，干扰素‑γ+ CD8+ T细胞和调节性T细胞数量显著降低，骨髓源性抑制细胞（MDSCs）数量显著增加。同时给予Gr-1中和抗体和UNC1999可以恢复抗肿瘤效果，并伴随CD8+ T细胞数量增加和MDSCs数量减少。趋化因子抗体芯片表明，与MDSC招募相关的趋化因子C5a、CCL8和CCL9的表达有所增强。综上，研究结果表明，EZH2抑制剂有助于减轻TME调控引起的肿瘤免疫力下降。EZH2抑制剂和减少MDSCs的药物的联合治疗可能代表了HCC的一种新的治疗策略。 版权所有 © 2023 Elsevier B.V.
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.Copyright © 2023 Elsevier B.V. All rights reserved.