Tim-3影响肾癌患者细胞免疫功能调节机制的研究

Kidney cancer is one of the most frequent cancer in urinary system, and the mechanism of its generation and development had caused people to pay wide attention. Recently domestic and international researches confirmed that Tim-3 had very important effects in cell immunoloregulation of tumor patients. The effects of Tim-3 and the tumor immunoregulation mechanism in kidney cancer were not reported yet. Our early researches indicated the polymorphism of Tim-3 gene had some relationship to the pathogenesy of kidney cancer,and we also discovered that the ratio of Tim-3+ cell in CD4+T lymphocyte and CD+8 T lymphocyte of kidney cancer patients had obviously increased ,compared to the ratio in health crowd. But the function and the action mechanism were still unknown. So we ratiocinate that Tim-3 possible influence the disease process by regulating cellular immune function in kidney cancer patients. We plan to research the distribution of Tim-3 , analysis the relation of Tim-3 to immunocyte(such as Th1,Th2, dendritic cells and CD4+、CD8+Treg) by some experiments(such as block or active Tim-3/galectin-9), and investigate the regulative effect and mechanism of Tim-3 in kidney cancer cytoimmunity in different stages of kidney cancer patients. We wish provide a new therapy target and theoretical basis for the biological therapy of kidney cancer.

肾癌是泌尿系统最常见的肿瘤之一，其发生发展机制目前受广泛关注。近年国内外研究证实Tim-3在肿瘤患者的细胞免疫调节中具有重要的作用。Tim-3及其参与的肿瘤免疫调节机制在肾癌中的作用目前尚无相关报道。我们前期研究发现Tim-3的基因多态性与肾癌发病有一定相关性，肾癌患者外周血CD4+T 细胞和CD+8 T细胞中Tim-3+细胞所占比例均有明显增加，但其功能与作用机制未明。我们推断Tim-3可能通过影响肾癌患者的细胞免疫功能影响疾病进程。本课题拟研究不同肾癌分期患者体内Tim-3的分布情况，通过阻断或激活Tim-3/galectin-9等试验，分析Tim-3与不同分期肾癌患者Th1、Th2、树突细胞、CD4+T、CD8+Treg等免疫细胞功能的关系，探讨Tim-3参与细胞免疫调节的作用及机制，从而为肾癌的生物治疗提供新的治疗靶点和理论依据。

肾细胞癌属于泌尿系统常见肿瘤，且发病率逐年上升。由于对其病理机制的不明确，各种治疗方法的疗效参差不齐。Tim-3是一类新型的细胞表面标志物，与PD-1十分类似。在免疫调节中发挥着重要作用。本课题深入探讨了Tim-3在肾细胞癌中的功能及作用机制。课题组首先发现了患者外周血CD4+T细胞表面的Tim-3较对照组上升。而肿瘤侵润CD4+T细胞表面的Tim-3则进一步明显上升。另外，而肿瘤侵润CD4+8细胞表面的Tim-3亦有显著上调。课题组进一步研究发现，肿瘤侵润淋巴细胞中Tim-3的表达预示着T-bet上升和IFN-g分泌减少，表明Tim-3可以定义肿瘤组织中功能衰退的一类细胞亚型。课题组更进一步研究了Tim-3在肾癌中的作用通路，发现Tim-3+的肿瘤侵润T淋巴细胞的Stat5和p38有明显障碍，暗示这两个通路是Tim-3发生作用的关键路径。课题组还探讨了调节Tim-3对肾细胞癌的治疗作用，明确了阻碍Tim-3 - Tim-3L可以显著提高肿瘤侵润CD4+和CD8+T细胞的功能效应。另外，课题组还发现了肾癌患者Tim-3水平与一类新型细胞亚型-调节性B细胞存在明显正向关联，而我们的数据显示调节性B细胞在肾癌中发挥抑制T细胞繁殖和抑制T细胞相关因子分泌等功能，暗示着Tim-3的另一条崭新的作用途径。总之，我们的结果显示了Tim-3在肾细胞癌中对于抑制免疫反应，促进肿瘤细胞生长等方面发挥着重要作用。因此通过抑制Tim-3途径而提高机体免疫反应将来可以作为一种有效的治疗肾癌的新疗法。此项研究的发现为这种疗法的开展打下有力的基础。