Toll样受体2在恶性胸腔积液中免疫调节作用及机制

Toll like receptor 2 (TLR2) is one of pathogen pattern recognition receptors that expressed on various cells including malignant cells. It is a critical molecule that participate both in innate immunity and adaptive immunity. Malignant pleural effusions (MPE) is caused by primary pleural tumors or pleural metastasis originating from adenocarcinomas of the lung, breast and ovary or by lymphomas. MPE is difficult to diagnose and treat. Many studies have shown correlations between TLR2 signaling and tumor proliferation, progression and metastasis, yet the immune regulation of TLR2 in MPE is unknown. In order to investigate the immune regulatory role of TLR2 in MPE, this study will use murine MPE as a research model to ① explore TLR2 expression on the surface of various immune cells in MPE; ② elucidate the impacts of both activation and deficiency of TLR2 on distribution of Th cells and signaling pathway mechanisms that how TLR2 regulates Th17/Treg cells balance in MPE; ③ explore the TLR2 on prognosis of MPE. This study will give insights into the mechanisms of MPE formation; elucidate whether TLR2 pathway is a novel therapeutic target for malignant disease; explore potential immunologic parameters for differentiating MPE from other pleural effusions.

Toll样受体2（TLR2）是可识别病原相关分子模式的受体之一，包括肿瘤细胞在内的多种细胞表面均可检测到TLR2，是固有免疫与适应性免疫反应中的关键分子。恶性胸腔积液（MPE）是原发肿瘤或肿瘤转移到胸膜腔所致，MPE的诊断和治疗目前都存在一定困难。已经发现TLR2与肿瘤增殖、进展和转移关系密切，而TLR2在MPE中作用的研究尚未见报道。为探讨TLR2在MPE中的作用机制，本项通过构建小鼠MPE模型，①确定在肿瘤微环境中各免疫细胞表达TLR2的情况；②探讨TLR2对MPE中Th亚群的分布和功能的影响及机制，TLR2与MPE中Th17/Treg平衡的关系及机制以及Th17、Treg与MPE的发生、发展的关系；③明确TLR2对MPE转归的影响。本项目将首次揭示TLR2在MPE中起到的免疫学调节作用；探讨TLR2通路能否作为晚期恶性肿瘤治疗的靶标；并找出对MPE具有鉴别诊断价值的免疫学指标。

Toll样受体2（TLR2）是可识别病原相关分子模式的受体之一，包括肿瘤细胞在内的多种细胞表面均可检测到TLR2，是固有免疫与适应性免疫反应中的关键分子。恶性胸腔积液（MPE）是原发肿瘤或肿瘤转移到胸膜腔所致，MPE的诊断和治疗目前都存在一定困难。已经发现TLR2与肿瘤增殖、进展和转移关系密切，而TLR2在MPE中作用的研究尚未见报道。本项目通过构建小鼠MPE模型，探讨TLR2对MPE中Th亚群的分布和功能的影响及机制。研究发现TLR2可促进恶性胸腔积液的发展，加速恶性胸腔积液小鼠的死亡。其机制是TLR2直接抑制Th17细胞分化，促进Th2细胞分化，并通过IL-17依赖机制间接抑制Th9细胞的分化。此外，TLR2通路通过促进IL-10的产生，抑制Th1细胞分化，进而促进小鼠MPE产生。另外，研究发现IL-10敲除小鼠MPE中一氧化氮（NO）的含量显著高于野生型（WT）小鼠，NO通过促进Th1细胞分化抑制胸水的形成。本项目首次揭示了TLR2信号通路促进MPE的发展及作用机制，建议阻断TLR2通路可能是预防或减轻癌症患者MPE的一种新方法。