Tim-3/Galectin-9信号通路在维吾尔族宫颈癌中介导的免疫逃避作用研究

The Uygurs are a nation of the high incidence of cervical cancer, But the lack of understanding of its pathogenesis hampered effective research in prevention.The Tim-3/Galectin-9 pathway can induce immune tolerance and play important roles in pathogenesis and tumor immune escape. However, the effect of Tim-3/Galectin-9 pathway on cervical cancer of Uygurs is still unclear. Previous studies showed that Treg cells involved in immune evasion of cervical cancer, but the mechanism is unclear. The project make immune negative regulation of Tim-3 / Galectin-9 pathway as the starting point, study Tim-3 / Galectin-9 signaling pathway activation before and after surgery and clinical outcomes in patients with cervical cancer and cervical cancer in tumor-bearing mice, to clarify its relationship with cervical cancer; by blocking Tim-3 ,analysis the role of Tim-3 / Galectin-9 signal pathway for effect and mechanism of CD8 + T cells in the immune Inhibition function ,state the role on the formation and maintain in cervical cancer immune escape pathway of Tim-3 / Galectin-9; through co-culture by Tim3 + Treg cells in vitro, analysis the action and mechanism of Tim-3 / Galectin-9 pathway directly or indirectly inhibit the activation of CD8 + T cells, clarify the relationship between this pathway and the development of cervical cancer,provide new ideas for prevention and treatment of cervical cancer in carriing out blocking immune evasion signaling pathways .

维吾尔族是宫颈癌高发民族，对其发生机制认识不足阻碍了有效防治的研究。Tim-3/Galectin-9通路在肿瘤免疫逃逸中发挥重要作用，但其在维吾尔族宫颈癌的作用尚未阐明。我们前期发现Treg细胞参与宫颈癌免疫逃逸，但其机制尚不清楚。本项目以Tim-3/Galectin-9通路的免疫负调控为切入点，研究手术前后及临床转归的宫颈癌患者和荷瘤小鼠Tim-3/Galectin-9通路的激活，明确其与宫颈癌的关系；通过Tim-3阻断，分析Tim-3/Galectin-9对CD8+T细胞的免疫功能中发挥的抑制作用及机制，阐明Tim-3/Galectin-9通路在宫颈癌免疫逃避形成和维持上所起的作用；通过Tim-3+Treg细胞体外共培养，分析Tim-3/Galectin-9通路直接或间接抑制CD8+T细胞功能，阐明该通路与宫颈癌发生发展的关系，为开展以阻断免疫逃避信号途径为靶点的宫颈癌防治提供新思路。

本研究从新疆维吾尔族宫颈病变HPV感染状况的研究和维吾尔族宫颈病变患者体内体外试验两方面入手，运用流式细胞检测、ELISA、RT-PCR、免疫组化和体外阻断实验等方法对HPV分型及Tim-3/Galectin-9 信号通路与宫颈癌的关系进行研究，开展手术前和手术后以及临床转归的宫颈癌患者Tim-3+CD4+T、Tim-3+CD8+T细胞的数量研究；并进一步研究Tim-3和Galectin-9的mRNA水平以及在宫颈组织中的表达。通过体外和小鼠实验，探讨Tim-3/Galectin-9 信号通路在宫颈癌患者免疫抑制状态形成和维持上所起到的作用，对深入开展宫颈癌免疫治疗具有重要的实验和理论指导作用。为进一步阐明HPV与宫颈癌免疫应答的关系并为提高疫苗的保护性效果提供理论依据。深入了解Tim-3/Galectin-9 信号通路与宫颈癌关系及机制将为临床防治宫颈癌提供新思路，为以后开展扭转宫颈癌免疫下调和免疫逃避寻找切入点奠定基础。