A34-31 Reprogramming of Pulmonary Neuroendocrine Cells Drives Eosinophilic COPD

Rationale

A subset of patients with chronic obstructive pulmonary disease (COPD) exhibits persistent peripheral eosinophilia and a distinct clinical phenotype, including differential responses to corticosteroids and biologics targeting type 2 inflammation. While blood eosinophils are used clinically to stratify these patients, the epithelial programs that sustain airway eosinophilia in COPD remain poorly defined. We hypothesized that distinct epithelial niches underlie eosinophilic COPD (EOS-COPD) and contribute to its unique immunologic and remodeling features.

Methods

We analyzed three complementary human cohorts using spatial transcriptomics and single-cell RNA sequencing (scRNA-seq). In Cohort 1, spatial transcriptomics was performed on peripheral lung resections from COPD patients stratified as EOS-COPD (blood eosinophils ≥300/µL) or non-eosinophilic COPD (NEOS-COPD; <300/µL; N = 64). Patients with blood eosinophils 150-300/µL were classified as NEOS-COPD, as lung eosinophil abundance in scRNA-seq data (Cohort 2; N = 61) did not differ from those with <150/µL. Differential expression and pathway enrichment analyses were integrated with scRNA-seq to define cell-type-specific transcriptional states, eosinophil subclusters, and candidate ligand-receptor interactions. Key findings were validated in an independent bronchial biopsy cohort (Manchester; Cohort 3; N = 41) with spatial regions of interest spanning epithelium, sub-epithelium (lamina propria), and submucosa.

Results

Spatial profiling revealed enrichment of pulmonary neuroendocrine cell (PNEC)-associated pathways in EOS-COPD, contrasting with myeloid-dominant programs in NEOS-COPD (A). scRNA-seq confirmed increased eosinophils, B cells, and innate lymphoid cells in EOS-COPD, whereas M2-like macrophages predominated in NEOS-COPD (B). While PNEC abundance did not differ between groups, EOS-COPD exhibited marked PNEC transcriptional reprogramming, characterized by reduced canonical neuroendocrine markers (ASCL1, GRP), induction of hypoxia and stress-response pathways (HIF1A, NR4A1),increased expression of eosinophil-supporting niche factors (POSTN, IGF1), and increased extracellular matrix remodeling mediators (TIMP2, ADAM17) (C). Single-cell analysis identified distinct eosinophil subsets expressing ITGAM and IGF1R, consistent with complementary adhesion/inflammatory and tissue-remodeling activation axes (D). In bronchial biopsies, EOS-COPD demonstrated submucosa-specific enrichment of PNECs, supporting niche relocation following epithelial remodeling (E).

Conclusions

Eosinophilic COPD is characterized by hypoxia-linked PNEC reprogramming, with loss of neuroendocrine identity and acquisition of a remodeling and eosinophil-supportive secretome (F). Targeting PNEC stress programs and downstream eosinophil-niche signaling axes may represent novel therapeutic strategies for eosinophilic COPD.

This abstract is funded by: NHLBI. Alpha one foundation, Sanofi-Regeneron, Astra-Zeneca