Spatial profiling reveals complex cellular responses of anti-IL5 treatment with mepolizumab in eosinophilic chronic rhinosinusitis with nasal polyposis.

Abstract

There is limited understanding of the impact of anti-IL5 treatment on nasal polyp tissue biology in chronic rhinosinusitis with nasal polyps (CRSwNP). This study examined nasal polyp tissue cellular proteome and transcriptome responses to anti-IL5 treatment in CRSwNP utilising spatial profiling. GeoMx™ Digital Spatial Profiling (DSP) of 80 proteins and 1,833 mRNA targets in the polyp stroma and the whole transcriptome (18,815 mRNA targets) in polyp epithelia was undertaken on sinonasal biopsies collected from 20 individuals with eosinophilic CRSwNP before and after 16 and 24 weeks of mepolizumab treatment. Anti-IL5 therapy in patients with eosinophilic CRSwNP had significant tissue biological impact. Treatment-related changes in polyp stroma proteins associated with checkpoint inhibition (PD-1), neutrophil degranulation (CD6b, CD44, STING1) and the innate immune system (CD14, CD68, STING, CD163) were identified in a protein interaction network. Transcriptionally, there were significant reductions in gene sets associated with the reactome-terms innate and adaptive immune system, neutrophil degranulation and TGFβ receptor signalling in epithelial to mesenchymal transition within polyp stroma, as well as enhancing antioxidant pathways. In polyp epithelia, increases in gene sets associated with the reactome-terms cilium assembly and keratinisation and a reduction in the regulation of KIT signalling were observed. Spatial profiling demonstrates that the effects of anti-IL5 treatment within nasal polyp tissue extend beyond simple eosinophil reduction to regulation of innate and adaptive immune cells and in improving epithelial barrier biology. The clinical relevance of changes to improved barrier function may relate to quality-of-life metrics observed previously with anti-IL5 treatment.