Background: Monocytes isolated from patients with Cystic fibrosis (CF) with at least one F508del mutation partially improved Pseudomonas aeruginosa phagocytosis and intracellular bacterial killing after few months of Kaftrio (elexacaftor-tezacaftor-ivacaftor) therapy1. A similar effect has been documented in monocyte derived macrophages2,3. In addition, CF monocytes showed an increase in CFTR protein, a reduction in inflammasome activation and IL-1b secretion4. Collectively, these results suggest that the therapeutic effects of Kaftrio are also extended to phagocytic cells. However, the available data are limited to a short-term analysis of the effects of Kaftrio on these cells. 1Cavinato et al., 2023 doi: 10.1183/13993003.00725-2022 2Zhang et al., 2023 doi: 10.1183/13993003.02861-2021 3Aridgides et al., 2023 doi: 10.1038/s41598-023-38300-9 4Gabillard-Lefort et al., 2022 doi: 10.1164/rccm.202106-1426OC Aims: In this study the effect of long term Kaftrio therapy (12-36 months) on CFTR expression and on the phagocytic activity of monocytes was assessed. Methods: 44 pwCF were enrolled in the study. Monocytes, isolated from peripheral blood, were analyzed ex vivo to evaluate P. aeruginosa phagocytosis by flow cytometry; additionally, CFTR, at both RNA and protein levels, were analyzed. Results: We observed that monocytes, isolated after 12-36 months of Kaftrio therapy, showed a significant increase of bacterial phagocytosis and CFTR protein expression with respect to the pre-therapy samples. Differently, CFTR mRNA levels remained unchanged. These results were also corroborated by a significant improvement of the CF clinical outcomes in the three years of therapy. Conclusions: These results suggest that the long term Kaftrio therapy has a positive impact on the activity of CF monocytes, which in turn may contribute to the overall effect of Kaftrio on lung disease. Furthermore, we confirmed a recovery of mature CFTR in phagocytic cells, suggesting that Kaftrio therapy promotes CFTR protein maturation also in immune cells.
CFTR expression is enhanced in innate immune cells of subjects under therapy with Kaftrio / Sangiorgi, G.; Cavinato, L.; Cristoferi, M.; Pastore, V.; Chiappetta, D.; Cimino, G.; Ascenzioni, F.; Del Porto, P.. - (2025). (Intervento presentato al convegno 18th European Cystic Fibrosis Young Investigators Meeting tenutosi a Paris, France).
CFTR expression is enhanced in innate immune cells of subjects under therapy with Kaftrio
Sangiorgi G.Primo
;Cavinato L.Secondo
;Cristoferi M.;Pastore V.;Chiappetta D.;Ascenzioni F.Penultimo
;Del Porto P.Ultimo
2025
Abstract
Background: Monocytes isolated from patients with Cystic fibrosis (CF) with at least one F508del mutation partially improved Pseudomonas aeruginosa phagocytosis and intracellular bacterial killing after few months of Kaftrio (elexacaftor-tezacaftor-ivacaftor) therapy1. A similar effect has been documented in monocyte derived macrophages2,3. In addition, CF monocytes showed an increase in CFTR protein, a reduction in inflammasome activation and IL-1b secretion4. Collectively, these results suggest that the therapeutic effects of Kaftrio are also extended to phagocytic cells. However, the available data are limited to a short-term analysis of the effects of Kaftrio on these cells. 1Cavinato et al., 2023 doi: 10.1183/13993003.00725-2022 2Zhang et al., 2023 doi: 10.1183/13993003.02861-2021 3Aridgides et al., 2023 doi: 10.1038/s41598-023-38300-9 4Gabillard-Lefort et al., 2022 doi: 10.1164/rccm.202106-1426OC Aims: In this study the effect of long term Kaftrio therapy (12-36 months) on CFTR expression and on the phagocytic activity of monocytes was assessed. Methods: 44 pwCF were enrolled in the study. Monocytes, isolated from peripheral blood, were analyzed ex vivo to evaluate P. aeruginosa phagocytosis by flow cytometry; additionally, CFTR, at both RNA and protein levels, were analyzed. Results: We observed that monocytes, isolated after 12-36 months of Kaftrio therapy, showed a significant increase of bacterial phagocytosis and CFTR protein expression with respect to the pre-therapy samples. Differently, CFTR mRNA levels remained unchanged. These results were also corroborated by a significant improvement of the CF clinical outcomes in the three years of therapy. Conclusions: These results suggest that the long term Kaftrio therapy has a positive impact on the activity of CF monocytes, which in turn may contribute to the overall effect of Kaftrio on lung disease. Furthermore, we confirmed a recovery of mature CFTR in phagocytic cells, suggesting that Kaftrio therapy promotes CFTR protein maturation also in immune cells.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
