肝癌组织中CD169阳性单核巨噬细胞的产生与调控机制

Monocytes/macrophages (Mφ) constitute a major component of antigen-presenting cells in the tissue. Because of the heterogeneity and plasticity, Mφ exhibit diverse functional phenotypes within different local microenvironment. Our recent study demonstrated that CD169 might be a candidate marker for an anti-tumoral functionally distinct Mφ subpopulation in hepatocellular carcinoma and other tumors. However, whether and how tumor microenvironment changes regulate the CD169+ Mφ differentiation and function is still unclear. In this project, we will combine clinical sample analysis and experimental studies to: 1). Evaluate the translational medical value of CD169+ Mφ in the tumor microenvironment of hepatocellular carcinoma. 2). Define the key immune cell subsets and target molecules, which can significantly affect the differentiation and transformation of CD169+ Mφ in cancer. 3). Elucidate the underlying mechanisms that regulate CD169+ Mφ differentiation and function by target molecules. 4). Explore the possibility to build anti-tumoral Mφ phenotype by key molecule or pathway manipulation. The results obtained from this project will not only help us to further understand the immunomodulatory mechanism of tumor associated monocytes/macrophages, but also provide molecular basis for development of immunotherapeutic strategies for treating hepatocellular carcinoma.

单核巨噬细胞（Mφ）是组织中数量最多的抗原递呈细胞。Mφ具有很强的异质性和可塑性，可根据局部微环境的变化而展现出不同的表型和功能。我们实验室在前期观察到：尽管实体瘤中的Mφ大多起着促肿瘤作用，然而在人肝癌等肿瘤组织中存在一类具有抗肿瘤功能的CD169+的Mφ亚群。但目前关于调控这类细胞在肿瘤组织微环境中产生和功能的机制尚不清楚。本项目拟结合临床样本、体外实验和动物模型，1）明确肝癌组织微环境中CD169+ Mφ在临床诊断和治疗过程中的转化医学价值；2）筛选并鉴定出可显著影响癌巢中CD169+ Mφ产生和转化的关键免疫细胞亚群和靶标分子；3）明确靶标分子的产生和效应机制，并探究调控靶标分子产生过程中的关键信号分子；4）探讨通过干预恢复癌巢中Mφ免疫活性来增强临床免疫治疗效果的可行性。所得结果不仅有助于我们更深入地认识肿瘤相关单核巨噬细胞的免疫调控机制，更可为肝癌的免疫治疗提供新的靶点和策略。

单核巨噬细胞（Mφ）是组织中数量最多的抗原递呈细胞。Mφ具有很强的异质性和可塑性，可根据局部微环境的变化而展现出不同的表型和功能。我们实验室在前期观察到：尽管实体瘤中的Mφ大多起着促肿瘤作用，然而在人肝癌等肿瘤组织中存在一类具有抗肿瘤功能的CD169+的Mφ亚群。但目前关于调控这类细胞在肿瘤组织微环境中产生和功能的机制尚不清楚。本项目紧密围绕肝癌组织微环境中CD169+ Mφ的产生与调控机制这一主题系统展开，基本完成既定的研究目标，明确了肝癌组织微环境中CD169+ Mφ能够作为独立的预后标志物指征患者更佳的预后状况；鉴定出I型干扰素是诱导癌巢中CD169+ Mφ极化的效应分子；并证明通过外源给予低剂量I 型干扰素能够有效抑制肿瘤进展，且联合PD-L1的阻断能够增强I型干扰素的抗肿瘤效果。所得结果可为研制以调控Mφ表型/功能或亚群为目标的新型防治策略提供理论基础。