Nasal Brushing Transcriptional Phenotypes Distinguish Type 2-high and -low Asthma in REGAIN, A Longitudinal Asthma Cohort

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Abstract RATIONALE: The molecular and cellular mechanisms underpinning therapeutic responses across all types of asthma are not understood. One challenge is the difficulty of performing airway sampling by sputum induction or bronchoscopy to adequately power integrative analyses. Transcriptional phenotyping of nasal brushings at scale provides a unique opportunity to help elucidate these mechanisms. In this work, we leveraged a large multimodal dataset from the REal-world and Genomic data-based Asthma Insights through Network analysis (REGAIN) study, a prospective, observational real-world study, to reveal novel insights into asthma pathogenesis, control, and remission. METHODS: Asthma patients enrolled in REGAIN were classified in 5 subgroups based on treatment, type 2 (T2) inflammation, and asthma control status, and followed up over 18 months. Healthy volunteers were recruited at baseline for cross-sectional comparison. Nasal brushing RNA samples were collected along with clinical data at study visits. Differential gene expression (DGE) analyses were performed comparing asthma patients and each asthma subgroup with healthy controls as well as asthma patients achieving remission vs. non-remission, followed by gene set enrichment analysis (GSEA) on a collection of 116 curated asthma signatures. Cell-type frequency in nasal brushing tissues were investigated using a deconvolution algorithm (BayesPrism). RESULTS: Transcriptomic and clinical data were acquired on 263 healthy volunteers and 528 asthma patients. Compared to healthy controls, DGE/GSEA revealed upregulation of known T2-specific signatures, such as eosinophils, basophils, FeNO production, and T2 immune responses across “T2-high” subgroups, but not in the “T2-low”. Gene sets associated with neutrophils, monocytes, innate immune signaling, and mucosal-associated invariant T (MAIT) cells were also specifically upregulated in “T2-high” subgroups. Meanwhile, “T2-high” and “T2-low” endotypes shared many features, including lower expression of epithelial ciliated cell function, T and B cell inflammation, and higher expression of genes involved in leukocyte trafficking and innate immune response. In the T2-high subgroup uncontrolled with at least two prior biologics, we identified a unique expression pattern involving upregulation of B cells, macrophages, ILC2s, gdT cells, dendritic cells, and mucous hypersecretion signatures. In the T2-high subgroup initiating de novo on biologics, we observed significantly higher baseline expression of ciliated cell signatures in patients achieving remission vs. non-remission. These observations were supported by cell frequencies derived from deconvolution analysis. CONCLUSIONS: Our results suggest that nasal brushing RNA samples can capture substantial portions of airway biology across type 2-high and -low asthma and implicates that ciliated epithelial cell restoration may be required for clinical remission in biological therapies.

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