ZHOU Yu,ZHANG Weiwei,GAO Youting. The sensitizing effect of targeting liver X receptor on PD-1 monoclonal antibody in the treatment of primary liver cancer[J]. JOURNAL OF WEZHOU MEDICAL UNIVERSITY, 2023, 53(1): 36-41.
Abstract：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 PD-L1 expression. In vivo study, The co-treatment strategy significantly enhanced the anti-tumor effect of single PD1 monotherapy 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.
