Synergistic effect of IFN-γ and IL-1β on PD-L1 expression in hepatocellular carcinoma

Immunotherapy using anti-programmed death 1 ligand 1 (PD-L1) antibodies has shown clinical efficacy against hepatocellular carcinoma (HCC) and is recognized as the first-line treatment for unresectable HCC. PD-L1 expression is affected by various cytokines produced by immune cells in the tumor microenvironment; howev-er, there is limited information about the effects of cytokine interactions on PD-L1 expression. In this study, we examined how cytokines induce PD-L1 expression in HCC cells. Both interferon gamma (IFN-gamma) and interleukin 1 beta (IL-1 beta) induced PD-L1 expression, and the two cytokines enhanced PD-L1 expression in combination compared to that when administered alone. The Janus kinase/signal transducer and activator of transcription signaling pathway activated by IFN-gamma is the major pathway of PD-L1 expression. The increase in interferon regulatory factor 1 expression and IFN-gamma receptor expression induced by IL-1 beta was associated with the synergistic effect of IFN-gamma and IL-1 beta on PD-L1 expression. These findings strongly indicate that IFN-gamma and IL-1 beta affect the mechanism underlying immune resistance in HCC cells.