Dipeptidyl Peptidase-1 Inhibition as a Novel Immunomodulatory Strategy in People with Bronchiectasis

Background The goal of this thesis was to explore the mechanism of action of a new anti-inflammatory treatment for bronchiectasis, the Dipeptidyl-peptidase-1 (DPP1) inhibitors, to seek biomarkers of treatment efficacy to guide ongoing development and clinical use. Methods This was achieved through three interlinked studies. Firstly, the neutrophil proteins Azurocidin-1 (AZU1), Olfactomedin-4 (OLFM4), the pro-inflammatory mucin MUC5AC, the antimicrobial peptides secretory leukoproteinase inhibitor (SLPI) and α-defensin-3, and a panel of inflammatory cytokines were measured in sputum supernatant from bronchiectasis patients from the WILLOW phase two trial of the DPP1 inhibitor brensocatib to measure response to treatment. Secondly, these markers were measured in stable bronchiectasis patients from the EMBARC-BRIDGE study to explore associations with disease severity, radiological and microbiological features. Finally, AZU1, OLFM4 and a broader inflammatory cytokine panel were measured in broncho-alveolar lavage from the BRILLIANT bronchiectasis study and related to neutrophil and cilia function and the microbiome. Results In the WILLOW trial, DPP1 inhibition with brensocatib reduced AZU1 and MUC5AC, increased SLPI and α-defensin-3 and altered multiple inflammatory cytokines. Baseline AZU1, OLFM4, and SLPI predicted enhanced treatment response. In EMBARC-BRIDGE, high AZU1, OLFM4 and proteinase-3 (PR3), and low SLPI and α-defensin-3 were associated with clinical disease severity, inflammatory radiological features and microbiome dysbiosis. Inflammatory cytokine clusters identified bronchiectasis endotypes associated with clinical and radiological features. In the BRILLIANT study, AZU1, OLFM4 and clusters of patients based on inflammatory cytokine profiles were indicative of inflammatory endotypes associated with altered neutrophil function, epithelial disruption, and reduced microbiome diversity. Conclusions This thesis identified novel immunomodulatory effects of DPP1 inhibition on multiple targets involved in inflammation, mucociliary clearance and host response to infection. It also identified novel biomarkers of treatment response and disease severity and explored effects of inflammation throughout the bronchiectasis vicious vortex. These findings shall guide ongoing development of DPP1 inhibitors and other anti-inflammatory treatments.