靶向肝X受体对PD-1单抗治疗原发性肝癌的增敏作用  

The sensitizing effect of targeting liver X receptor on PD-1 monoclonal antibody in the treatment of primary liver cancer

作　　者：周宇 张伟伟 高悠婷 ZHOU Yu;ZHANG Weiwei;GAO Youting(Department of Infectious Diseases,the Third Affiliated Hospital of Wenzhou Medical University,Wenzhou 325200,China)

机构地区：[1]温州医科大学附属第三医院感染科,浙江温州325200

出　　处：《温州医科大学学报》2023年第1期36-41,共6页Journal of Wenzhou Medical University

基　　金：浙江省医药卫生科技计划项目(2020KY927);浙江省自然科学基金项目(LY21H160009)。

摘　　要：目的:探索原发性肝癌中肝脏X受体(LXR)与程序性死亡配体1(PD-L1)表达的相关性;明确LXR激动剂(T09)对于PD-1单抗治疗的影响。方法:采用生物信息分析方法分析肝癌中LXR及其下游关键基因ATP结合盒转运体A1(ABCA1)表达和PD-L1表达的相关性。采用免疫组化染色在肝癌组织样本中验证LXR和PD-L1蛋白水平表达的相关性。采用慢病毒介导的RNA干扰技术分析肝癌细胞中LXR沉默对PD-L1蛋白水平表达的影响。建立免疫健全小鼠C57BL/6小鼠Hepa1-6肝癌原位瘤移植模型,分别给予T09和(或)PD-1单抗治疗,测量干预3周后的各组皮下瘤体积。结果:生物信息结果显示,LXR(r=0.20,P=0.021)及其下游关键基因ABCA1(r=0.12,P<0.001)表达和PD-L1表达呈正相关。免疫组化结果显示,高表达LXR的患者往往合并PD-L1高表达,两者表达具有相关性,差异有统计学意义(P<0.05)。通过慢病毒介导的RNA干扰技术敲低了肝癌细胞系中LXR的表达后,PD-L1的表达水平亦显著下调。动物实验显示与对照组、T09组、PD-1单抗组相比,T09+PD-1单抗组小鼠皮下瘤体积显著减小(P<0.001)。结论:肝癌中LXR表达与PD-L1表达具有显著相关性,LXR激动剂可以显著增加PD-1单抗治疗肝癌的敏感性。Objective:To investigate the correlation between liver X receptor(LXR)and programmed death-ligand 1(PD-L1)expression and the sensitizing effect of the agonist of LXR(T09)on the therapeutic effect PD1 monoclonal antibody against primary hepatocellular carcinoma(HCC).Methods:Bioinformatics analysis was applied in the present study to identify the correlation between the expression of LXR associated with its downstream target ABCA1 and the expression of PD-L1 in HCC.In addition,the protein level correlation between LXR and PD-L1 in liver cancer tissue samples was examined by immunohistochemical staining.The impact of hepatocellular carcinoma cells-derived LXR on PD-L1 expression was identify by knockdown of LXR using lentivirus-mediated siRNA.In vivo study,the orthotopic liver cancer transplantation mice model(Hepa1-6)mice were treated with T09 and(or)PD1 monoclonal antibody,and the subcutaneous tumor volume was measured after 3-week-intervention.Results:Bioinformatic analysis showed that the expression of LXR and ABCA1 was significantly correlated with the expression of PD-L1(correlation co-efficient r=0.12,P=0.021;Correlation co-efficient between LXR expression and PD-L1 expression,r=0.20,P<0.001).Immunohistochemical staining showed that both the expression levels of LXR and PD-L1 were significantly increased in tumor tissues.Patients with high expression of LXR were often associated with high expression of PD-L1.Immunohistochemical Chi-square test analysis showed that the expression of PD-L1 and LXR was correlated,with significant difference(P<0.05).Additionally,knockdown of LXR expression in HCC cell lines was associated with the decreased PDL1 expression.In vivo study,The co-treatment strategy significantly enhanced the anti-tumor effect of single PD1monotherapy treatment strategy.Conclusion:The expression of LXR was significantly correlated with PD-L1,and the agonist of LXR could significantly increase the sensitivity of PD1 in the treatment of liver cancer.

关 键 词：原发性肝癌 肝脏X受体 程序性死亡配体1 ATP结合盒转运体A1 

分 类 号：R735.7[医药卫生—肿瘤]