IL-17/IL-17RA Axis Facilitates Immune Evasion in Hepatocellular Carcinoma by Upregulating PD-L1 via the NF-κB Pathway.

BACKGROUND

The immunosuppressive tumor microenvironment in hepatocellular carcinoma (HCC) limits therapeutic efficacy. This study aimed to develop an immune-related signature for risk stratification and to identify key molecules that drive immune evasion.

METHODS

Transcriptomic data from HCC were analyzed to identify immune-related genes. A prognostic risk signature was constructed using Cox and least absolute shrinkage and selection operator regression and validated in an independent external cohort. Immune cell infiltration, immune checkpoints, and interleukin (IL)-17RA expression were characterized. Serum IL-17 levels were measured in patients with HCC, patients with cirrhosis, and healthy controls. Mechanistic studies included analyses of cell proliferation, programmed death-ligand 1 (PD-L1) expression, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, and the effects of IL-17RA knockdown.

RESULTS

A six-gene risk signature stratified patients into high- and low-risk groups. The high-risk group exhibited poorer prognosis and a more immunosuppressive microenvironment. External validation confirmed model robustness, with the risk score as an independent prognostic factor (multivariable Cox, P < 0.05). IL-17RA was overexpressed in HCC and correlated with poor prognosis, immune checkpoints, and M2 macrophage infiltration. Serum IL-17 levels were elevated in patients with HCC, had diagnostic value (area under the curve [AUC] = 0.738), and predicted vascular invasion (AUC = 0.891). Mechanistically, IL-17 activated NF-κB, increased p-p65, induced p65 nuclear translocation, upregulated PD-L1, and stimulated HCC cell proliferation. Pharmacological NF-κB inhibition or genetic silencing of IL-17RA abrogated IL-17-induced PD-L1 upregulation.

CONCLUSION

The six-gene prognostic signature and external validation suggest clinical utility. The IL-17/ IL-17 receptor alpha axis may drive immune escape by upregulating PD-L1 via NF-κB activation; therefore, it represents a potential prognostic biomarker and therapeutic target.