Long-term therapy with elexacaftor/tezacaftor/ivacaftor improves cystic fibrosis lung disease and monocyte function

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) therapy rapidly improves monocyte antimicrobial activity in people with cystic fibrosis (pwCF). Here, we investigated the effect of long-term ETI therapy on Pseudomonas aeruginosa phagocytosis and on CFTR expression and function in monocytes. Methods: Clinical information and biospecimens were obtained from 60 pwCF at initiation and after 12-48 months of ETI therapy. Monocyte phagocytosis was evaluated by flow cytometry after infection of PBMCs with P. aeruginosa expressing GFP. CFTR protein and mRNA levels were assessed by Western blot and qRT-PCR respectively. CFTR channel activity was evaluated by halide efflux assay. For comparison, measurements were also performed in non-CF subjects. Results: Longitudinal analysis of the clinical parameters confirmed an improvement of lung function and microbiology from 12 months and up to 48 months after the initiation of ETI therapy. ETI therapy resulted in a significant increase in monocyte P. aeruginosa phagocytosis reaching levels similar to non-CF monocytes. A significant increase in the levels of CFTR protein but not mRNA was observed in monocytes during the first 12-36 months of ETI therapy compared to pre-therapy. The expression of CFTR protein and channel function remained significantly lower than those of non-CF monocytes during ETI therapy. Conclusion: Our data suggest that the beneficial clinical effect of long-term ETI therapy is accompanied by an increase in monocyte P. aeruginosa phagocytosis while the CFTR protein expression and function remain lower with respect to non-CF monocytes.