Journal Article

Modulation of immune responses by elexacaftor/tezacaftor/ivacaftor therapy in cystic fibrosis: data from a compassionate use program

Sabbioni, Giuseppe, Fabrizzi, Benedetta, Altieri, Maria Teresa, Menichetti, Giacomo, Pianazzola, Anna, Lucca, Francesca, Borgatti, Monica, Cipolli, Marco, Tridello, Gloria, Lippi, Giuseppe, Ros, Mirco, Bezzerri, Valentino, Hristodor, Anca Manuela, De Luca, Erik, Meneghelli, Ilaria, Ferretti, Elisabetta, Bordicchia, Marica, Breveglieri, Giulia, Catanzaro, Giuseppina

2026

Overview

Background Elexacaftor-tezacaftor-ivacaftor (ETI) improves clinical outcomes in people with Cystic Fibrosis (pwCF), with possible anti-inflammatory properties. However, the molecular mechanisms underlying these effects remain unclear. This study investigates ETI’s anti-inflammatory and immunomodulatory activity, focusing on essential signaling pathways. Methods Forty-nine pwCF were followed for 24 months. PwCF underwent clinical and pulmonary function assessment along with sweat test chloride measurement. Blood samples were analyzed for red and white blood cell counts and C-reactive protein (CRP). Plasma cytokines were quantified and phospho-kinase arrays and western blotting were used to assess protein phosphorylation in peripheral blood mononuclear cells (PBMC) from pwCF and healthy controls, pre- and post-ETI. Gene expression was evaluated in patient-derived PBMC and CF bronchial epithelial cells in vitro. Results ETI treatment significantly improved percent-predicted forced expiratory volume in 1 s (ppFEV1) and reduced intravenous antibiotic use. Inflammatory markers (including CRP) and circulating leukocytes decreased, especially lymphocytes and monocytes. Six of 27 pro-inflammatory cytokines were significantly downregulated. ETI strongly inhibited Signal Transducer and Activator of Transcription 5 (STAT5) phosphorylation in PBMC and CF epithelial cells, both in vivo and in vitro. This correlated with reduced interleukin IL-6, IL-8, and TNF-α mRNA levels. Pharmacological inhibition of JAK/STAT mimicked ETI effects on cytokine expression, supporting STAT5 as an important player involved in CF chronic inflammation. Conclusion Long-term ETI treatment confirms clinical benefits and exerts measurable immunomodulatory effects, partially via inhibition of JAK/STAT signaling. These findings support its broader impact beyond CFTR correction. Further studies are warranted to explore long-term immunological outcomes, especially in younger patients initiating early therapy.

• Publisher: BioMed Central,Nature Publishing Group,BMC
• Subject: Adolescent / Adult / Aminophenols - administration & dosage / Aminophenols - therapeutic use / Anti-inflammatory agents / Benzodioxoles - administration & dosage / Benzodioxoles - therapeutic use / Blood / C-reactive protein / Cells, Cultured / CFTR modulators / Chemokines / Chloride Channel Agonists / Clinical trials / Cystic fibrosis / Cystic Fibrosis - diagnosis / Cystic Fibrosis - drug therapy / Cystic Fibrosis - immunology / Cytokines / Drug Combinations / Elexacaftor / Epithelial cells / Epithelium / Female / Gene expression / Humans / Immune response / Immunology / Immunomodulation / In vivo methods and tests / Indoles - administration & dosage / Indoles - therapeutic use / Inflammation / Kinases / Leukocytes / Leukocytes (mononuclear) / Leukocytes, Mononuclear - drug effects / Leukocytes, Mononuclear - immunology / Leukocytes, Mononuclear - metabolism / Ligands / Lymphocytes / Male / Medicine / Medicine & Public Health / Molecular modelling / Monocytes / Mutation / Neutrophils / Patients / Pediatrics / Peripheral blood mononuclear cells / Phosphorylation / Pneumology/Respiratory System / Proteins / Pulmonary functions / Pyrazoles - administration & dosage / Pyrazoles - therapeutic use / Pyridines - administration & dosage / Pyridines - therapeutic use / Pyrrolidines - administration & dosage / Pyrrolidines - therapeutic use / Quinolones - administration & dosage / Quinolones - therapeutic use / Respiratory function / Software / STAT5 / Stat5 protein / Treatment Outcome / Tumor necrosis factor-TNF / Tumor necrosis factor-α / Western blotting / Young Adult