肝癌对PD-1/PD-L1免疫治疗的反应率仍然较低，肿瘤中CD8+T细胞的浸润程度与其疗效密切相关。我们研究发现：肝癌患者组织中CD8+T细胞数量与Notch1的表达负相关；在肝癌细胞中沉默Notch1可促进T细胞对其杀伤。进一步探索发现Notch1可沉默共刺激因子ICAM1的表达。已知缺乏共刺激信号会导致T细胞失能、肿瘤组织中CD8+T细胞减少。据此我们假设Notch1可沉默ICAM1诱导肝癌免疫治疗耐受。本项目拟①进一步探明肝癌患者组织中Notch1/ICAM1的表达与免疫治疗耐受的相关性；②通过慢病毒载体/靶向去唾液酸糖蛋白受体的纳米药物载体调控肝癌细胞Notch1/ICAM1的表达，在体外探讨其对T细胞活化和杀伤作用的影响，在荷瘤动物模型中探明其对PD-1/PD-L1单抗及AFP特异性TCR-T治疗效果的影响。本研究有助于了解肝癌免疫治疗耐受的机制，为提高肝癌免疫治疗的效果提供依据

The objective response rate of immunotherapy for liver cancer with PD-1/PD-L1 antibody blockade is still low. The extent of CD8+ T cell infiltration in tumor tissue is closely related to the objective response. Our previous results showed that the extent of CD8+ T cell infiltration was negatively correlated with Notch1 expression and knocking down of Notch1 in hepatoma cells can enhance the killing ability of T cells. Further exploration showed that Notch1 can silence the expression of costimulatory molecule ICAM1. It has been reported that deficiency of costimulatory molecules can lead to disability of T cell and decrease of CD8+ T cell infiltration. Given the above, we assumed that Notch1 could induce immunotherapy tolerance in liver cancer via silencing costimulatory molecule ICAM1. In this project, firstly we propose to verify the correlation between Notch1/ICAM1 expression and immunotherapy tolerance in liver cancer. Next, the expression of Notch1/ICAM1 was regulated by lentiviral vector or Nano-drug delivery vehicles that targeting asialoglycoprotein receptor. And lastly, the effect of Notch1/ICAM1 on the activation and killing ability of T cell was investigated in vitro. Meanwhile, the influence of Notch1/ICAM1 to the immunotherapy with PD-1/PD-L1 antibody blockade or AFP-specific TCR-T cells was investigated in vivo. This project aims to elucidate the mechanism of immunotherapy tolerance, and to provide basis for improving the effect of immunotherapy for hepatocellular carcinoma.