Proteomics profiling of inflammatory responses to elexacaftor/tezacaftor/ivacaftor in cystic fibrosis

Front Immunol. 2025 Jan 28:16:1486784. doi: 10.3389/fimmu.2025.1486784. eCollection 2025.

Abstract

Background: CFTR modulator therapies have positive clinical outcomes, yet chronic inflammation and bacterial infections persist in people with CF (pwCF). How elexacaftor-tezacaftor-ivacaftor (ETI) fails to improve innate immune signaling responsible for bacterial clearance and inflammation resolution remains unknown.

Methods: We used an unbiased proteomics approach to measure the effect of ETI on inflammatory proteins. Plasma from 20 pediatric pwCF and 20 non-CF (NCF) was collected during routine examination and 3 months after ETI initiation. Protein screening was performed with an inflammation panel (Target 96, Olink®). Bioinformatics analysis was used to determine changes in protein expression.

Results: There were significantly fewer pulmonary exacerbations after ETI initiation, along with sustained improvement in lung function and reduced bacterial colonization. Unpaired analysis of CF pre-ETI and NCF resulted in 34 significantly different proteins. Of these, CCL20, MMP-10, EN-RAGE, and AXIN1 had a log2 fold change of 1.2 or more. There was a modest shift in overall CF protein profiles post-ETI toward the NCF cluster. Unpaired analysis of protein differential expression between NCF and CF post-ETI identified a total of 24 proteins significantly impacted by ETI therapy (p-value ≤ 0.05), with only CCL20 having a log2 fold change higher than 1.2. Paired analysis (CF pre- and CF post-ETI) of differential protein expression demonstrated significant expression changes of MMP-10, EN-RAGE, and IL-17A. Pathway analysis identified significantly impacted pathways such as the NF-κB pathway.

Conclusion: This study showed that ETI in a pediatric cohort had a modest effect on several inflammatory proteins with potential as biomarkers. Pathways significantly impacted by ETI can be further studied for future therapies to combat persistent inflammation and dysregulated immunity.

Keywords: NF-κB; cystic fibrosis; inflammation; modulators; proteomics.

MeSH terms

  • Adolescent
  • Aminophenols* / therapeutic use
  • Benzodioxoles* / therapeutic use
  • Child
  • Chloride Channel Agonists / therapeutic use
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Cystic Fibrosis* / drug therapy
  • Cystic Fibrosis* / immunology
  • Cystic Fibrosis* / metabolism
  • Drug Combinations
  • Female
  • Humans
  • Indoles* / therapeutic use
  • Inflammation* / drug therapy
  • Inflammation* / metabolism
  • Male
  • Proteomics* / methods
  • Pyrazoles* / therapeutic use
  • Pyridines* / therapeutic use
  • Pyrrolidines* / therapeutic use
  • Quinolones* / therapeutic use

Substances

  • Aminophenols
  • Quinolones
  • Benzodioxoles
  • Drug Combinations
  • Indoles
  • Pyrazoles
  • ivacaftor
  • Pyridines
  • Pyrrolidines
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Chloride Channel Agonists

Associated data

  • figshare/10.6084/m9.figshare.28255481.v1