抗PD-1抗体在肝癌免疫治疗中的关键耐药机制及干预研究

近年来，以抗PD-1抗体为代表的肿瘤免疫治疗已成为肝癌最主要的治疗手段之一。但其总体客观缓解率（ORR）不到20%。我们前期研究发现：1）肝癌循环肿瘤细胞（CTC）与原位肿瘤基因表型高度一致，可实时反映其功能状态并与抗PD-1抗体疗效密切相关；2）抗PD-1抗体耐药后CTC中Hippo/YAP通路相关分子及TIM3等表达显著增加；3）部分联用干扰素-α的肝癌患者，其ORR可提高一倍以上；4）体外预实验提示干扰素-α可能通过影响肿瘤免疫微环境增敏抗PD-1抗体疗效。本课题将在大量预实验基础上，1）进一步探索肝癌CTC与抗PD-1抗体耐药的相关性及其内在机制，筛选临床可用的特征性耐药分子标签；2）分析肿瘤免疫微环境变化在抗PD-1抗体耐药中的作用机制。3）深入研究干扰素-α增敏抗PD-1抗体的作用机制，为后续临床应用打下基础。

In recent years, tumor immunotherapy represented by anti-PD-1 antibody has become one of the most important treatment methods for liver cancer. However, the overall objective remission rate (ORR) is less than 20%. Our previous studies found that: 1) circulating tumor cells (CTC) of liver cancer are highly consistent with in situ tumor gene phenotype, which can reflect their functional status in real time and is closely related to the therapeutic effect of anti-PD-1 antibody; 2) The expression of Hippo/YAP pathway related molecules and TIM3 etc. in CTC increased significantly after anti-PD-1 antibody resistance. 3) The ORR of some liver cancer patients combined with interferon-α can be more than doubled; 4) Pre-experiment in vitro suggests that interferon-α may enhance the therapeutic effect of anti-PD-1 antibody by affecting tumor immune microenvironment. On the basis of a large number of preliminary experiments, this subject will 1) further explore the correlation between CTC and anti-PD-1 antibody drug resistance in liver cancer and its internal mechanism, and screen clinically applicable characteristic drug resistance molecular tags; 2) To analyze the mechanism of tumor immune microenvironment changes in anti-PD-1 antibody drug resistance. 3) In-depth study on the mechanism of interferon-α sensitizing anti-PD-1 antibody to lay a foundation for subsequent clinical application.