D108-06 Fatty Acid Binding Protein 4-Positive Alveolar Macrophage Depletion in Emphysema-Associated Lung Cancer

Rationale Patients with chronic obstructive pulmonary disease (COPD), including its emphysema phenotype, face a significantly elevated risk of developing non-small cell lung cancer (NSCLC). The progression from emphysema to NSCLC represents a critical yet poorly understood clinical transition. Elucidating the cellular drivers of this process is essential for developing early intervention strategies for high-risk patients. Methods We established a single-cell transcriptomic atlas using human lung tissue from a cohort comprising 6 non-smokers, 6 smokers, 6 smokers with emphysema, 4 smokers with NSCLC, and 8 smokers with both emphysema and NSCLC. Time-series gene expression clustering analysis was employed to identify co-expression modules dynamically altered during disease progression. Subsequent analyses included cell proportion quantification, pseudotime trajectory inference, and cell-cell communication network analysis. Results Our analysis identified a gene module that was progressively upregulated along the disease spectrum from non-smokers through smokers to patients with emphysema. This module was functionally enriched for oxidative phosphorylation and cellular respiration pathways and specifically defined a distinct subpopulation of Fatty Acid Binding Protein 4-positive alveolar macrophages (FABP4+ AMs). Quantification of cellular abundance revealed a significant expansion of FABP4+ AMs in smokers and smokers with emphysema, followed by a marked decrease in patients with emphysema-NSCLC. Pseudotime analysis suggested a transition of FABP4+ AMs from a protective state toward functional exhaustion in the tumor context. Cell-cell communication analysis further demonstrated a shift from protective interactions in emphysema to immunosuppressive signaling dominated by TGF-β in the NSCLC microenvironment. Conclusion Our findings reveal that the depletion of FABP4+ AMs is a key cellular event marking the transition from emphysema to NSCLC. The dramatic loss of this specific macrophage population represents a potential cellular biomarker for stratifying lung cancer risk in emphysema patients, offering a critical insight for early clinical detection.