Towards Asthma Remission: Integrative Network Analysis Implicates Mucous-ciliated Cell Dynamics in Response to Biologic Therapies in the REGAIN Cohort

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Abstract RATIONALE: Clinical remission is increasingly the goal of asthma treatment, however therapeutic response and mechanisms underpinning remission are poorly understood. To advance mechanistic understanding of treatment response in asthma, we conducted the RE al-world and G enomic data-based A sthma I nsights through N etwork analysis (REGAIN) study, a prospective, observational real world asthma study combining clinical, molecular, and digital health data. METHODS: REGAIN enrolled adult patients with asthma in 5 subgroups based on type 2 (T2) inflammation and treatment. We generated genetic and transcriptomic data from nasal brushing samples to complement clinical data. We constructed a multi-modal Bayesian causal network of asthma which was combined with weighted gene co-expression network analysis in a hybrid graph to capture dynamic cell-cell interactions related to clinical outcomes. Clinical remission at 6 months was defined as Asthma Control Test (ACT) ≥ 20, no exacerbations, and no use of chronic oral corticosteroids for asthma. RESULTS: We recruited 791 individuals in the initial analysis (528 asthma and 263 healthy). Participants with asthma included (1) T2-high on inhaled therapy (n=178), (2) T2-high on biologics (n=134), (3) T2-low on inhaled therapy (n=105), (4) T2-high newly initiated on biologics (T2denovo, n=58), and (5) T2-high who failed treatment with at least 2 biologics (n=35). From an integrated network analysis, we identified a central role of goblet, ciliated, and mucous-ciliated cells in asthma severity and remission in response to biologics. Higher baseline ciliated cell frequency was observed in patients with asthma achieving remission vs. non-remission in T2denovo subgroup. Further, mucous-ciliated cell frequency increased in those achieving remission vs. non-remission after 6 months of biologics treatment. To better understand the role of mucous-ciliated cells in therapeutic response, we employed air-liquid interface cultured airway epithelial cell organoids chronically exposed to IL-13 to model airway epithelium changes associated with chronic severe asthma. Removal of IL-13, to model therapeutic intervention, led to resolution of goblet cell metaplasia via differentiation of goblet cells into mucous-ciliated cells and was associated with restoration of ciliation, confirming our network-derived hypothesis. Conclusions: Mucous-ciliated cell frequency increased in those achieving remission vs. those in non-remission with biologic therapy, implying that mucous-ciliated epithelial cells may play a role in the restoration of airway homeostasis in asthma. Collectively, these data suggest that following biologic-induced suppression of airway inflammation, ciliated epithelial cell restoration is required to achieve clinical remission, establishing a framework for understanding mechanisms underlying asthma remission

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