肝移植后Th17-Treg转分化促进肝癌复发转移的机制研究

肝移植术后肝癌复发转移与移植后机体免疫状态密切相关。本课题组前期研究发现Th17参与肝移植排斥反应。Th17近年来被发现可以转分化为其他T细胞亚群，导致功能转变。我们的前期研究发现小鼠肝移植后Th17-Treg转分化增强，且从Th17转化来的Treg较常规Treg具有更强的促癌作用。我们还发现小鼠肝移植后IL-33表达升高。研究表明IL-33具有促进Treg分化的作用。因此，我们推测肝移植后IL-33水平升高促进了Th17-Treg转分化，继而促进肝移植后肝癌复发转移，基于IL-33在这一过程中的关键作用，其可作为潜在的干预靶点。目前Th17-Treg转分化在肝移植术后肝癌复发转移中的作用尚不清楚。本项目拟明确肝移植后Th17-Treg转分化的机制及其对肝癌复发转移的影响作用，分析促进Th17-Treg转分化的关键细胞因子和信号通路，为探寻移植术后肝癌复发转移的干预靶点奠定基础。

The recurrence and metastasis of hepatocellular carcinoma after liver transplant are closely associated with post-transplant immune status. We found that Th17 cells were activated during graft rejection. Recent studies showed that Th17 cells could transdifferentiate to other T cell subtypes, which lead to the changes of their functions. Our previous studies showed that murine liver transplantation enhanced Th17-Treg conversion and the pro-tumor functions of Tregs transdifferentiated from Th17 are stronger than normal Tregs. We also observed that murine IL-33 level was increased after liver transplantation, which have been showed to promote Treg differentiation. Thus, we hypothesized that liver transplantation promotes Th17-Treg transdifferentiation via IL-33，which induces hepatocellular carcinoma recurrence and metastasis. And IL-33 could be the therapeutic target. It remains elusive that whether this conversion impact the recurrence and metastasis of hepatocellular carcinoma after liver transplant. This project would use animal models and clinical samples to investigate the mechanisms of Th17-Treg transdifferentiation and its impacts on immune responses and the recurrence and metastasis of hepatocellular carcinoma. Moreover, we will analyze the key cytokines，signaling pathways，and therapeutic targets of this process. Finally, we will clarify its clinical significance. Our aim is to clarify the mechanisms of Th17-Treg transdifferentiation in promoting hepatocellular carcinoma after liver transplantation, which could provide new therapeutic targets for the treatments.