Background: Sputum proteomics is a powerful analytical technique for identifying important mechanisms of airway diseases. We applied this approach to a cystic fibrosis (CF) cohort commencing elexacaftor/tezacaftor/ivacaftor (ETI), a cystic fibrosis conductance regulator (CFTR) modulator responsible for dramatic clinical improvements. We hypothesised that ETI would shift the proteome so it more closely resembled health.
Methods: Spontaneous sputa was sampled from CF subjects pre and once receiving ETI (n=21) and compared to CF (n=6) and healthy (n=15) control sputum. Samples were analysed by bottom-up shotgun proteomics using liquid-chromatography/mass spectrometry.
Results: Following ETI therapy, mean FEV1% increased by 15% (SD 7.8). Obvious sputum proteome changes were seen during ETI therapy, but patients remained distinct from healthy controls, even subjects achieving normal lung function. Proteome changes during ETI appear driven by dysregulated immune responses with reductions in neutrophil activity and restoration of counterregulatory responses. Although the abundance of neutrophil-derived proteins largely reduced, there were important respiratory proteases that were minimally responsive to ETI, including proteinase 3, cathepsin G and matrix metallopeptidase 9, identified by equivalence testing.
Conclusions: Reduction in neutrophilic airway inflammation may contribute to clinical response seen with CFTR modulation. However, for most subjects receiving ETI inflammation persists and some disease mechanisms may not be adequately addressed. This suggests a possible role for additional anti-inflammatory therapies for patients receiving ETI, as well as those currently ineligible for CFTR modulation therapy.