肿瘤微环境中大量髓系来源的抑制性细胞（MDSCs）的浸润是肝细胞癌（HCC）免疫逃逸的重要因素，而阐明其浸润机制有望建立HCC治疗新策略。本课题组前期研究发现，IRF8在肝癌细胞中表达下调，且与患者不良预后密切相关；过表达IRF8显著抑制HCC进展，延缓生存期，并抑制MDSCs向瘤组织浸润，推测肝癌细胞IRF8下调可增强MDSCs介导的免疫逃逸从而促进HCC恶性进展。本项目拟：（1）采用RNA-Seq、蛋白质组学等技术，阐明肝细胞IRF8表达缺失的主要原因及分子机制；（2）采用CHIP-Seq、反向蛋白质芯片等技术分析肝癌细胞IRF8缺失介导的趋化因子表达谱的变化，寻找调控MDSCs浸润的关键分子并阐明其调控机制；（3）筛选特异性靶向IRF8的小分子激动剂用于HCC的实验性治疗。通过上述研究，阐明HCC中调控MDSCs浸润的关键分子事件，为新型肝癌治疗药物的研发提供理论基础和实验依据。

Progressive infiltration of myeloid-derived suppressor cells (MDSCs) to the tumor microenvironment in Hepatocellular carcinoma (HCC) is considered as a key factor for the escaping of the cell from immune surveillance. The key modulators and the underlying mechanisms of MDSCs is new strategy for development of HCC therapy. Based on analysis of clinical samples and animal models, our pre-experiment results showed that IRF8 is significantly decreased in hepatoma cells than normal hepatocytes, which was closely related to HCC. We have also found that hepatic IRF8 overexpression can inhibit the progression of HCC by suppressing the infiltration of MDSCs into tumor tissues. It is speculated that loss of hepatic IRF8 expression takes part in infiltration and accumulation of MDSCs to enhance the MDSCs-mediated immune escape and promote tumorigenesis. This project intends to carry out the following contents: (1) To explore the factors and mechanisms of IRF8 expression in HCC progression. (2) To elucidate the molecular mechanism of IRF8 deregulation-induced infiltration of MDSCs. (3) Screening of small molecular agonists targeting IRF8 based on the mechanism discovered in this project. In summary, this project will clarify key molecular event that disruption of IRF8 in hepatoma cell promote the progression of hepatocellular carcinoma by inducing chemotaxis of MDSCs, and provide the theoretical basis and experimental basis for the development of new HCC therapeutic drugs.