盐诱导激酶2调控肝癌微环境中肿瘤免疫反应及机制的研究

肝癌免疫环境直接影响免疫治疗效果。代谢激酶对肿瘤免疫环境和免疫检查点抑制剂起重要调控作用，但机制不清楚。本项目前期通过测序发现抗PD-1治疗效果较好肝癌患者组织中盐诱导激酶2（salt inducible kinase 2，SIK2）表达显著降低，而且SIK2在肝癌细胞及组织中表达升高，且与患者临床分期正相关，敲低SIK2显著抑制肝癌生长和转移。据此推测：在肝癌患者中，代谢激酶SIK2表达显著升高，通过相关信号通路阻碍肝癌中CD8+细胞富集，抑制SIK2可通过调节免疫相关信号通路增强肝癌部位CD8+T细胞的密度，从而影响肝癌抗PD-1抗体治疗肝癌效果。本课题将用SIK2基因敲除小鼠、BALB/C裸鼠肝癌移植瘤模型和肝癌肺转移模型，去验证SIK2对免疫反应的调控、敲除或抑制SIK2对抗PD-1抗体体内抗肝癌的影响及探讨SIK2调控肝癌微环境中肿瘤免疫反应分子机制，为免疫治疗提供新的理论依据

The immune environment of liver cancer directly affects the effect of immunotherapy. Metabolic kinases play an important role in regulating the tumor immune environment and immune checkpoint inhibitors, but the mechanism is not clear. In the early stage of this project, sequencing found that the anti-PD-1 treatment effect is better. The expression of salt inducible kinase 2 (SIK2) in liver cancer patients is significantly reduced, and the expression of SIK2 is increased in liver cancer cells and tissues Clinical stage is positively correlated, knocking down SIK2 significantly inhibits the growth and metastasis of liver cancer. Based on this, we speculate that: in patients with liver cancer, the expression of metabolic kinase SIK2 is significantly increased, and the accumulation of CD8+ cells in liver cancer is hindered through related signaling pathways. Inhibiting SIK2 can enhance the density of CD8+ T cells in liver cancer sites by regulating immune-related signaling pathways. Thereby affecting the effect of liver cancer anti-PD-1 antibody treatment of liver cancer. This subject will use SIK2 gene knockout mice, BALB / C nude mouse liver cancer transplantation model and liver cancer lung metastasis model to verify the regulation of SIK2 on immune response, knockout or inhibition of SIK2 anti-PD-1 antibody in vivo against liver cancer And to explore the molecular mechanism of SIK2 regulating tumor immune response in the microenvironment of liver cancer, providing a new theoretical basis for immunotherapy