Baseline IL-6, IL-8, IFN-ω, and perforin as prognostic biomarkers in immune checkpoint inhibitor-treated metastatic non-small cell lung cancer

Background: Prognostic serum biomarkers of immune checkpoint inhibitor (ICI) efficacy in non-small cell lung cancer (NSCLC) are sparse. We evaluated baseline cytokines as markers of outcomes in ICI-treated metastatic NSCLC.

Methods: Baseline serum cytokines were quantified in 96 patients with metastatic NSCLC receiving ICIs. Separate multivariable models were fit for progression-free survival (PFS) and overall survival (OS), adjusting for clinical covariates. Hazard ratios (HRs) were expressed per doubling in cytokine concentration. Significant cytokines were then incorporated into multivariable Cox models, and model discrimination was assessed using time-dependent area under the curve (AUC). Latent class analysis (LCA) was performed to identify cytokine-defined patient phenotypes associated with survival.

Results: Each doubling of interleukin-6 (IL-6) increased the hazard of death by 34% [HR =1.34; 95% confidence interval (CI): 1.13–1.60; P<0.001] and interleukin-8 (IL-8) by 36% (HR =1.36; 95% CI: 1.16–1.59; P<0.001). Conversely, each doubling of interferon-omega (IFN-ω) (HR =0.87; 95% CI: 0.80–0.95; P=0.001) and perforin (HR =0.50; 95% CI: 0.33–0.76; P<0.001) decreased mortality risk. Multivariable cytokine models incorporating IL-6, IL-8, IFN-ω, and perforin achieved time-dependent AUCs >0.70 for PFS and OS. LCA identified two cytokine classes: one enriched for IL-6/IL-8 (poor outcomes) and another enriched for IFN-ω/perforin (favorable outcomes).

Conclusions: Higher baseline serum IL-6 and IL-8 concentrations were associated with inferior survival, whereas higher baseline serum IFN-ω and perforin were associated with improved survival in ICI-treated metastatic NSCLC, defining distinct host immune-inflammatory phenotypes with prognostic relevance.