肝癌组织中巨噬细胞来源的IL-17E对B细胞浸润与分化的影响机制

IL-17E is a pro-inflammatory cytokine that plays an important role in the development and progression of allergic diseases. However, the origin, molecular mechanisms and biological functions of IL-17E-positive cells in human solid tumors are now completely unclear. In previous studies, we found that IL-17E-positive cells were abundantly present in human hepatocellular carcinoma (HCC) and were mainly macrophages. Furthermore, we found that the density of intratumoral IL-17E-positive cells was positively correlated with tumor size in HCC patients. Moreover, we also observed a co-localization of IL-17E-positive cells, B cells and plasma cells in the tumor areas of HCC and there was a positive correlation among the three. We will combine the clinical sample analysis and experimental studies to: 1). Explore the effects and underlying mechanisms of IL-17E on tumor immune microenvironment and tumor progression, focusing on whether and how IL-17E participate in B cell infiltration and differentiation; 2). Characterize the specific nature of B cells context that determine their ability to facilitate or prevent tumor growth; 3). Define the key molecules/markers that regulate the development of human tumors with paired tissue sample collected from different stages of disease progression. The results obtained from this project will not only be the first to reveal the machanisms about how IL-17E regulate tumor progression, but also provide a theoretical basis for the development of IL-17E ,B cells and plasma cells as novel targets for cancer prevention and cure.

IL-17E在变应性疾病的发生、发展中起重要作用。目前，关于IL-17E阳性细胞在人实体瘤组织的来源，诱导机制及生物学功能还完全不清楚。我们前期发现：IL-17E阳性细胞在人肝癌组织中大量存在，而且主要是巨噬细胞，它们的数量与肿瘤大小呈正相关。进一步分析表明，IL-17E阳性细胞与B细胞、浆细胞分布较为一致，而且三者在数量上呈正相关。在此基础上，本课题拟结合临床样本分析及体外模型，来研究IL-17E对肿瘤免疫微环境的塑造及对肿瘤进展的影响及潜在机制，其中重点探讨IL-17E是否以及如何参与B细胞浸润及分化；初步阐明B细胞影响肿瘤退化/进展的关键因素；在临床样本中验证相关表型/信号分子与血管生成、临床分期和预后的相关性。所得结果不仅率先揭示了IL-17E调控肿瘤进展的机制，还可为研制以IL-17E、B细胞和浆细胞为靶标的肿瘤分子分期标准和新型防治手段提供理论基础。

IL-17E是重要的促炎症因子，在寄生虫感染及过敏性疾病的发病中发挥着重要的作用。但目前关于IL-17E如何参与肿瘤的发生发展还不清楚。我们的前期研究观察到：IL-17E阳性细胞在人肝癌组织中大量存在，而且主要是巨噬细胞，它们的数量与肿瘤大小呈正相关。通过进一步的临床样本分析及体外实验，我们研究了肝癌组织中IL-17E阳性细胞的表型及与其与肿瘤分期、复发和生存的相关性，重点探讨了IL-17E是否以及如何参与B细胞浸润及分化，进而调控炎症网络影响肿瘤进展的机制。我们发现：肝癌癌巢浸润的IL-17E阳性细胞密度与患者的总体生存时间呈负相关；肝癌组织中IL-17E阳性细胞与B细胞、浆细胞分布较为一致，而且三者在数量上呈正相关；肝癌细胞表达IL-17E的受体IL-17RB，IL-17E通过促进肝癌细胞分泌趋化因子CXCL9、CXCL10和CXCL11招募CXCR3+B细胞并诱导其分化成熟，促进肿瘤发生发展。所得结果不仅率先揭示了IL-17E调控B细胞影响肿瘤进展的机制，还可为研制以IL-17E、B细胞和浆细胞为靶标的肿瘤分子分期标准和新型防治手段提供理论基础。