细胞因子TNFSF15对肿瘤淋巴系统形成及其功能的调控机制

The goal of the proposed research is to determine the mechanism of action of tumor necrosis factor superfamily 15 (TNFSF15) in the modulation of lymphatic vessel growth in solid tumors. There are two types of lymphatic structures in tumors: tumor-associated lymphatic vessels which allow cancer cell dissemination, and tertiary lymphoid structures (TLS) with congregated lymphocytes which are critical for tumor-related immune responses. TLS-associated biomarkers are of prognostic value in favor of patient survival in many types of cancers. We found that TNFSF15 can inhibit the activities of vascular endothelial growth factor (VEGF) receptor-1 (VEGFR1) and receptor-2 (VEGFR2). We further found that TNFSF15 stimulates lymphatic endothelial cell (LEC) growth, facilitates lymphatic vessel growth in embryos, and promotes LEC to express vascular endothelial growth factor receptor 3 (VEGFR3) gene, which is a major player in the regulation of LEC growth. Based on these findings we hypothesize that TNFSF15 promotes lymphatic system formation in tumors, and that this may be utilized to assist cancer immunotherapy. There are three specific aims in this study: 1) To determine what receptor or receptor complex on LEC specifically mediates TNFSF15 signals; 2) To determine how TNFSF15 dictates the fate of the cells that take part in lymphangiogenesis; and 3) To determine how TNFSF15 modulates the genesis and functions of TLS. The results of this study will bring forward highly desirable insights into the molecular mechanism that modulates the development and function of tumor lymphatic systems, especially with regard to the role of TLS in cancer immunity.

本项目旨在揭示细胞因子TNFSF15对实体瘤淋巴系统形成及其功能的调控机制。实体瘤淋巴系统包括肿瘤相关淋巴管和瘤内三级淋巴样结构（tertiary lymphoid structures; TLS）。临床上TLS相关标志物与乳腺癌等多种癌症的患者良好预后正相关。我们发现TNFSF15能够抑制血管内皮生长因子受体VGEFR1和VEGFR2的活性，同时促进淋巴管内皮细胞LEC中VEGFR3的表达，促进LEC生长，促进小鼠胚胎淋巴管发育。我们的假说是：TNFSF15对肿瘤淋巴系统特别是TLS的形成和功能有重要促进作用。本项目将研究：1）TNFSF15在LEC上的特异受体是什么；2）TNFSF15怎样参与决定淋巴管新生时的前体细胞命运；3）TNFSF15怎样调控TLS的生成和功能。研究结果将深化对淋巴管发育生长调控机制以及TLS的形成和功能的认识，并为临床利用肿瘤免疫反应提供新的理论。

恶性肿瘤是危害人类健康的重大疾病。肿瘤微环境中的血管和淋巴管组成了复杂的脉管系统，是各种药物和细胞进出肿瘤组织的主要通道，其稳态调节直接影响肿瘤恶性进展、放化疗抵抗、靶向和免疫治疗效果。实体瘤淋巴系统包括肿瘤相关淋巴管和瘤内三级淋巴样结构。临床上TLS相关标志物与乳腺癌等多种癌症的患者良好预后正相关。我们围绕TNFSF15调节肿瘤微环境中脉管系统的稳态及相关的生理病理过程开展工作。在肿瘤实验模型中发现了肿瘤微环境内淋巴管和淋巴内皮祖细胞在TNFSF15处理下的变化情况，通过细胞生物学和分子生物学手段分析了相关基因的调节规律，这对我们理解肿瘤微环境脉管系统中淋巴管系统的稳态调节规律提供了新证据。我们在血管母细胞瘤和脑出血后急性损伤等需要综合调节血管和淋巴管系统的疾病模型中研究了TNFSF15重组蛋白的干预效果和作用机制。同时，我们紧密围绕肿瘤免疫微环境开展应用基础研究，在TNFSF15调节髓系细胞分化、血管内皮细胞间质转化的调节机制方面取得了重要进展，为解析TLS行程和肿瘤免疫微环境改善提供了新理论。为了长期解决包括靶点探寻、靶向递送、条件释放等研究和应用难点，我们还进行了化学生物学方面的尝试，为进一步开展工作提供了重要手段。本项目成果共发表SCI论文11篇，授权专利3项。培养博士生6名，硕士生5名。

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