EZH2调控C/EBPε介导荷瘤状态下MDSC的产生及机制研究

The cancer development and progress can be attributed to the combined change of gene and immunity. Therefore, it is important to consider these two factors when treating malignant tumors. Our previous study suggest that EZH2 inhibitor (GSK126) cannot inhibit the tumor growth in non-immunodeficiency mice; and the reason lies in the increase of MDSC from bone marrow precursor cells ,which restrains antitumor immunity to offset of GSK126’s effect on tumor cells. Based on our mechanism research and related articles, we propose that GSK126 selectively inhibit EZH2 and promote myeloid precursor differentiation to MDSC through up-regulating C/EBPε and then affecting C-myb or C-myc. In this project, EZH2-cKO mice were used to validate the above phenotype and C/EBPε chemical blockers were used to elucidate the molecular mechanism of EZH2 in regulating the production of MDSC. MDSC deletion drugs to be explored to enhance the effect of EZH2 inhibitor on tumor therapy. This project not only will benefit to understand the molecular mechanism of EZH2 regulating MDSC in tumor-bearing mice, but also give a new understanding of the EZH2 inhibitor on the antitumor immunity and may provide effective combination treatment strategy.

肿瘤的发生发展是基因及免疫功能改变的共同结果，因此，抗肿瘤治疗时全面考虑两者的影响至关重要。本项目前期发现：EZH2抑制剂（GSK126）在裸鼠中抗瘤效果显著，但在C57小鼠中无抗瘤效应，其原因是其在杀伤肿瘤的同时，显著促进骨髓前体细胞向MDSC分化，抑制抗肿瘤免疫，导致抗瘤失败。结合相关文献申请者推测：GSK126选择性抑制EZH2，上调C/EBPε表达，促进髓系前体细胞向MDSC分化增多。本项目拟在前期工作基础上，通过EZH2特异性敲除小鼠，进一步明确EZH2在调控MDSC中的作用；通过C/EBPε抗体阻断实验明确EZH2调控MDSC产生的分子机制；并初步探讨联合清除MDSC药物增强EZH2抑制剂抗瘤应答的治疗策略。通过本研究，不但能阐明EZH2调控荷瘤状态下MDSC产生的分子机制，也将开启EZH2抑制剂对抗肿瘤免疫功能影响的新认识，为提高EZH2抑制剂临床疗效提供有效的联合治疗策略。

肿瘤的发生发展是基因及免疫功能改变的共同结果，因此，抗肿瘤治疗时全面考虑两者的影响至关重要。EZH2（zeste 同源物增强子）是基因表达的关键表观遗传调节因子，并且在多种癌症中过表达。我们研究发现EZH2抑制剂（GSK126）在裸鼠中抗瘤效果显著，但在C57小鼠中无抗瘤效应。进一步我们发现使用 EZH2 抑制剂 GSK126 抑制 EZH2 活性，可导致髓源性抑制细胞 (MDSC) 数量增加和参与抗肿瘤免疫的 CD4+ 和 IFN-γ+CD8+ T 细胞数量减少。Anti-Gr-1抗体或吉西他滨/5-氟尿嘧啶药物清除MDSC后可减轻 MDSC 介导的免疫抑制，并增加 CD4+ 和 CD8+ T 细胞肿瘤浸润和 GSK126 的抗肿瘤效果。从机制上讲，我们发现了肿瘤状态下中 MDSC 产生的新途径，其中 抑制EZH2 促进骨髓从原始造血祖细胞向髓系的分化。这些研究表明，调节肿瘤免疫微环境可能会提高 EZH2 抑制剂的疗效。将开启EZH2抑制剂对抗肿瘤免疫 功能影响的新认识，为提高EZH2抑制剂临床疗效提供有效的联合治疗策略。