Published online Jan 15, 2025. doi: 10.4251/wjgo.v17.i1.97831
Revised: September 2, 2024
Accepted: October 28, 2024
Published online: January 15, 2025
Processing time: 184 Days and 20.5 Hours
Hepatocellular carcinoma (HCC) is an inflammation-associated tumor with a dismal prognosis. Immunotherapy has become an important treatment strategy for HCC, as immunity is closely related to inflammation in the tumor microenvironment. Inflammation regulates the expression of programmed death ligand-1 (PD-L1) in the immunosuppressive tumor microenvironment and affects im
To investigate the effect and mechanism of action of IL-17A on PD-L1 expression and to identify attractive candidates for the treatment of HCC.
The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR, western blotting, and flow cytometry. Mechanistic studies were conducted with gene knockout models and pathway inhibitors. The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells. The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro, and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.
IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner, whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A. IL-17A enhanced the survival of HCC cells in the coculture system. IL-17A increased the viability, G2/M ratio, and migration of HCC cells and decreased the apoptotic index. Cyclin D1, VEGF, MMP9, and Bcl-1 expression increased after IL-17A treatment, whereas BAX expression decreased. The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8 + T lymphocyte infiltration in an HCC mouse model.
IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapentaplegic 2 signaling pathway in HCC cells. Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.
Core Tip: Overexpression of programmed death ligand-1 (PD-L1) on tumor cells promotes cancer immune escape through inhibiting T cell function. Interleukin-17A (IL-17A) can increase the expression of PD-L1 in tumor cells and promote tumor progression. However, related research in hepatocellular carcinoma (HCC) is scarce. We clarified a novel mechanism by which IL-17A upregulated PD-L1 expression in HCC cells by the IL-17A receptor/phosphorylation-small mothers against decapentaplegic 2 axis. IL-17A could drive immune escape and promote proliferation, migration, and angiogenesis of HCC cells while inhibiting the apoptosis of HCC cells. IL-17A inhibition enhanced the therapeutic efficacy of the PD-L1 antibody in HCC in vivo.