Tumour hepcidin levels as a biomarker for predicting response to immune checkpoint inhibition in advanced non-small cell lung cancer

Abstract

Background

Hepcidin, a key regulator of iron homeostasis, is often overexpressed in non-small cell lung cancer (NSCLC). While hepcidin renders cells susceptible to ferroptosis, which is linked to the activity of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors, its clinical impact on immunotherapy efficacy remains unclear.

Methods

We retrospectively analyzed patients with advanced NSCLC who received anti-PD-1/PD-L1 monotherapy. Patients were stratified into two groups based on immunohistochemical analysis: high hepcidin expression (tumour proportion score [TPS] = 50%, n = 6) and none-to-moderate expression (TPS 0–49%, n = 39). Treatment duration, progression-free survival (PFS), and overall survival (OS) were compared. In vitro mechanisms were also explored using hepcidin and interferon-gamma (IFNg) co-culture models.

Results

The high-hepcidin group exhibited a longer median treatment duration (42 vs. 5 days; p = 0.051). This group also showed improved PFS (2222 vs. 126 days; hazard ratio [HR], 0.35 [95% CI, 0.16–0.79]; p = 0.0643) and OS (not reached vs. 459 days; HR, 0.46 [95% CI, 0.18–1.16]; p = 0.0994), although these differences did not reach statistical significance. In vitro experiments revealed that hepcidin enhanced IFNg-induced reactive oxygen species production and cytotoxicity in A549 cells.

Conclusion

Advanced NSCLC patients with high hepcidin expression may derive greater benefit from anti-PD-1/PD-L1 monotherapy. Our findings suggest that cellular sensitivity to IFNg varies by hepcidin expression levels.