Abstract 64P
Background
Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor with abnormal growth factor pathway and poor prognosis. Immune checkpoint inhibitors (ICIs) for HCC are rarely effective and lack biomarkers. Therefore, it is of great significance to search for new biomarkers for HCC immunotherapy to further improve the efficacy of ICIs.
Methods
We collected tissue specimens and clinical data of 20 cases of HCC treated with anti-PD-1 therapy, and detected the expression of growth factors FGF19, IGF2, TGF-β, EGF, IL-6, HGF-β, and PD-L1, etc., by using IHC method. We further collected serum specimens from 116 HCC samples who had been treated with anti-PD-1 therapy and detected the expression of FGF19 using ELISA assay. We also analyzed 523 HCC samples in a tissue microarray by immunohistochemistry. Liver cancer cell line cells were used and analyzed by immunoblot, immunofluorescence, and immunoprecipitation assays. C57/BL6 mice with subcutaneous tumors grown from Hep1-6 cells were given combinations of FGFR4 inhibitors with anti-CTLA-4 therapy or alone; tumors and survivals were collected and analyzed.
Results
We observed that high expression of FGF19 in tissues and serum of HCC cases was correlated with good therapeutic effect of anti-PD-1 therapy, and FGF19 was positively correlated with the expression of PD-L1. In vitro experiments showed that FGF19 activated the PI3K-Akt pathway, increased the phosphorylation of GSK3β at Ser9, and weakened the ubiquitination of PD-L1 to stabilize its expression. The up-regulated expression of PD-L1 enhanced its binding with PD-1, and weakened the ability of activated PBMCs to kill tumor cells. In subcutaneous tumor model in immune-competent mice, FGFR4 inhibitors with anti-CTLA-4 therapy decreased tumor growth and prolonged survival of mice compared with anti- CTLA-4 or FGFR4 inhibitors alone.
Conclusions
FGF19 promotes HCC immune evasion by regulating PI3K-Akt-GSK3β pathway to maintain PD-L1 stability. FGF19 can also be used as a potential marker for screening HCC immunotherapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Jing-ping Yun.
Funding
This study was supported by the National Natural science foundation of China (No. 8220302 and No. 82303879); Science and Techmology Plamning Proiect of Guangzhou (No. 2023A0412137, No. 2023A0411777).
Disclosure
All authors have declared no conflicts of interest.