肿瘤间充质干细胞通过CCL22影响非小细胞肺癌化疗敏感性的机制研究

项目名称： 肿瘤间充质干细胞通过CCL22影响非小细胞肺癌化疗敏感性的机制研究

项目编号： No.81502615

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 刘延国

作者单位： 山东大学

项目金额： 18万元

中文摘要： 晚期非小细胞肺癌化疗的有效率较低，影响化疗药物敏感性的因素和机制尚不明确。前期研究发现给予肺癌荷瘤小鼠注射间充质干细胞（MSCs）可导致肿瘤对顺铂敏感性下降，进一步分析发现顺铂可显著上调CCL22在MSCs的表达，但其机制及与化疗敏感性的关系尚不清楚。CCL22是趋化Treg至肿瘤局部的关键因子，而化疗引发的损伤信号可激活Toll样受体（TLRs），后者参与多种趋化/细胞因子的调控；因此我们推测顺铂化疗引发损伤信号的释放，激活MSCs表面的TLRs、促进其CCL22表达，继而介导Treg向肿瘤局部募集，从而降低顺铂敏感性。本课题拟系统研究MSCs对顺铂敏感性的影响，探讨TLRs-CCL22-Treg在其中的作用和参与机制，并分析NSCLC患者Treg浸润、CCL22表达与化疗疗效的相关性；研究将有助于明确肿瘤微环境特别是MSCs在顺铂化疗敏感性中的作用，为化疗敏感性预测和提高提供理论依据。

中文关键词： C05_气管；支气管；肺肿瘤；化学药物治疗敏感性；间充质干细胞；CCL22；调节性T细胞

英文摘要： The chemotherapy response rate in non-small cell lung caner (NSCLC) patients is relatively low, however, the involved mechanisms remain largely unknown. Our preliminary study demonstrated that mesenchymal stem cell (MSCs) reduced chemosensitivity to cisplatin in mouse bearing lung cancer xenografts and CCL22 expression in MSCs was remarkably up-regulated by cisplatin treatment; but the regulating mechanism of CCL22 and its contribution to lower chemosensitivity to cisplatin are obscure and need to be further elucidated. CCL22 is a key chemokine for recruiting Treg to tumor microenvironment; the damage signals induced by chemotherapy could activate Toll-like receptors (TLRs), which subsequently promote the release of chemokines and cytokines. Thus we speculate the damage signals induced by cisplatin treatment would activate TLRs in MSCs and increase the expression of CCL22, which results in accumulation of Treg into tumor microenvironment and reduced sensitivity to cisplatin. In the present project, we intend to systematically investigate the role of MSCs in chemosensitivity to cisplatin and explore the possible mechanisms involved in this process, especially via recruitment of Treg by CCL22 through TLRs activation. Besides, we will analyze the correlation between Treg infiltration, plasma CCL22 level and cisplatin efficacy in advanced NSCLC patients. Our study may help to further reveal the role of tumor microenvironment, especially MSCs, and underlying mechanisms in modulating chemosensitivity to cisplatin, which will provide clues for the prediction and improvement of chemosensitivity.

英文关键词： Lung cancer;Chemosensitivity;Mesenchymal stem cells;CCL22;Regulatory T cell