What question did this study set out to answer?

This research aims to explore the effects of Elexacaftor/Tezacaftor/Ivacaftor therapy on inflammatory responses in immune cells of cystic fibrosis patients.

May 20, 2026

B33-11 Single-Cell RNA-Sequencing Reveals Deactivation of Inflammatory Responses in Cystic Fibrosis Classical Monocytes Following Elexacaftor/Tezacaftor/Ivacaftor Therapy

Key Points

This research aims to explore the effects of Elexacaftor/Tezacaftor/Ivacaftor therapy on inflammatory responses in immune cells of cystic fibrosis patients.
Conducted single-cell RNA-sequencing on PBMC and lung explant tissues from healthy and cystic fibrosis donors.
Utilized bioinformatics for quality control, clustering, differential gene expression, and pathway analysis.
Compared inflammatory responses in classical monocytes before and after ETI therapy.
Significant suppression of LPS signaling, NF-κB, and MAPK/AP-1 pathways was observed in monocytes post-ETI therapy.
Down-regulation of CD14, TREM1 co-receptors and cytokines IL-1β and CXCL8 was noted, indicating reduced pro-inflammatory activity.
IL-1β production was normalized after therapy, highlighting potential biomarker opportunities.

Abstract

Abstract Chronic infections pose a significant challenge to people with Cystic Fibrosis (PwCF), contributing to considerable health complications. The combination medication of Elexacaftor/Tezacaftor/Ivacaftor is well known for its ability to restore lung function; however, the transcriptomic changes in CFTR-expressing immune cells by ETI treatment remains unclear, particularly its role in the regulation of infections and inflammation by CF immunocytes. We performed single-cell RNA-sequencing of PBMC and lung explant tissues from health and PwCF donors. Bioinformatics methods were used for QC, clustering, differential gene expression, and pathway analysis. Our analysis highlighted suppression of key inflammatory pathways in PBMC classical monocytes three months following ETI therapy, including lipopolysaccharide (LPS) signaling, NF-κB, MAPK/AP-1 cascades, and pro-inflammatory cytokine production. Notably, LPS co-receptors CD14 and TREM1, as well as cytokines IL-1β and CXCL8, were significantly down-regulated. Our sequencing analysis also suggests a decrease in classical monocyte migration, adhesion, and apoptotic abilities. Subsequent CF versus healthy control comparison in lung explants shows elevated inflammatory response in classical monocytes amongst pre-ETI PwCF, led by the upregulation of IL-1β. ETI therapy reprograms their transcriptomic landscape, suppressing key pro-inflammatory pathways, including the LPS/NF-κB axis. Importantly, IL-1β production was normalized. These findings highlight a potential immunomodulatory mechanism underlying ETI’s clinical benefits and offer valuable opportunities for biomarker discovery. This abstract is funded by: NHLBI and CFF

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