Decoding the spatial and microenvironmental control of pathogenic innate lymphoid cell dynamics in COPD and associated exacerbations to define novel therapeutic interventions

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease characterised by emphysema, airway remodelling and acute exacerbations (AECOPD) that significantly increase mortality risk. In-depth understanding of complex immune networks in a heterogenous patient group is mandatory to elucidate novel therapeutic targets. Innate lymphoid cells (ILCs) are critical regulators of mucosal immunity, exhibiting pronounced phenotypic and functional heterogeneity shaped by local microenvironmental cues. Dysregulated ILCs are central to the pathogenesis of numerous chronic lung diseases, yet their contribution to COPD remains poorly defined. The in-depth phenotypic, functional and molecular mechanisms defining true ILC heterogeneity, the pulmonary niche supporting ILCs, and the processes underlying ILC-mediated tissue pathology in COPD/AECOPD are yet to be identified. Using unique patient samples, complementary mouse models, and patient-derived lung-organoids, I will integrate high-dimensional full-spectrum flow cytometry with spatial and transcriptional profiling to determine how tissue-specific microenvironmental cues and bi-directional crosstalk with neighbouring stromal-immune networks shape ILC function and promote tissue injury. By defining the signals driving pathogenic ILC states, and the capacity of these ILCs to perturbate their local microenvironment to perpetuate lung injury, I will provide the first unequivocal evidence for how ILCs drive facets of COPD pathogenesis, revealing novel therapeutic avenues for COPD/AECOPD.