Serum C-C motif chemokine ligand 17 as a predictive biomarker for the progression of non-idiopathic pulmonary fibrosis interstitial lung disease.

Abstract

Background: Interstitial lung disease (ILD), represented by idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF), shows poor prognosis due to progressive fibrosis. Early therapeutic intervention is required to enhance the efficacy of antifibrotic drugs, highlighting the importance of early detection of ILD progression. Although candidate biomarkers for predicting ILD progression have been recently reported through omics analyses, clinically measurable biomarkers remain unestablished. This study aimed to identify clinically measurable biomarkers that could predict the degree of ILD progression.

Methods: The serum levels of 13 candidate biomarkers were prospectively measured by chemiluminescent enzyme immunoassay and the utilities for predicting ILD progression were compared in the discovery cohort (total 252 patients). Moreover, we evaluated the utility of the identified biomarker in another independent cohort (154 patients with non-IPF-ILD) and examined the dynamics of the biomarker by immunoblotting and single-cell RNA sequencing (scRNA-seq) using samples of patients and a mouse model.

Results: In the discovery cohort, C-C motif chemokine ligand (CCL)17 could reliably predict ILD progression, particularly in patients with ILD other than IPF, and showed significant associations with mortality (hazard ratio [HR] 3.70; 95% confidence interval [CI] 1.19-11.49; P = 0.015; cut-off value = 418 pg/mL). Consistently, in the validation cohort, the CCL17 high group showed significantly higher mortality (HR: 2.15; 95% CI 0.99-4.69; P = 0.049), and CCL17 was identified as an independent prognostic factor from corticosteroid or immunosuppressive agents use and ILD-gender-age-physiology index. Similar to the results of serum studies, CCL17 levels in the lungs of patients with PPF and model mice were higher than those in controls. They were positively correlated with CCL17 levels in the serum, suggesting that the increased serum CCL17 levels could reflect an increase in CCL17 levels in lung tissues. The scRNA-seq analysis of lung tissues from model mice suggested that the levels of CCL17 derived primarily from conventional dendritic cells and macrophages increased, especially during the profibrotic phase.

Conclusions: We identified serum CCL17 as a clinically measurable biomarker for predicting non-IPF-ILD progression. Serum CCL17 could enable the stratification of patients at risk of non-IPF-ILD progression, leading to appropriate early therapeutic intervention.