BACKGROUND
Abnormal macrophage function caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is a critical contributor to chronic airway infections and inflammation in people with cystic fibrosis (PWCF). Elexacaftor/tezacaftor/ivacaftor (ETI) is a new CFTR modulator therapy for PWCF. Host-pathogen and clinical responses to CFTR modulators are poorly described. We sought to determine how ETI impacts macrophage CFTR function, resulting effector functions, and relationships to clinical outcome changes.
METHODS
Clinical information and/or biospecimens were obtained at ETI initiation and 3-, 6-, 9, and 12-months post-ETI in 56 PWCF and compared to non-CF controls. Peripheral blood monocyte-derived macrophages (MDMs) were isolated and functional assays performed.
RESULTS
ETI treatment was associated with increased CF MDM CFTR expression, function, and localization to the plasma membrane. CF MDM phagocytosis, intracellular killing of CF pathogens, and efferocytosis of apoptotic neutrophils was partially restored by ETI, but inflammatory cytokine production remained unchanged. Clinical outcomes including increased FEV1 (+10%) and BMI (+1.0) showed fluctuations over time and were highly individualized. Significant correlations between post-ETI MDM CFTR function and sweat chloride levels were observed. However, MDM CFTR function correlated with clinical outcomes better than sweat chloride.
CONCLUSIONS
ETI is associated with unique changes in innate immune function and clinical outcomes.