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Spatial profiling reveals complex inflammatory responses of anti-IL5 treatment with mepolizumab in eosinophilic chronic rhinosinusitis with nasal polyposis
  • +6
  • Nicholas West,
  • Sarah Williams M,
  • James Sinclair,
  • Peter Howarth,
  • Pete Smith,
  • Raquel Alvarado ,
  • Peter Earls,
  • Richard Harvey,
  • Amanda Cox
Nicholas West
Griffith University School of Pharmacy and Medical Sciences

Corresponding Author:[email protected]

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Sarah Williams M
The University of Queensland
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James Sinclair
Griffith University School of Pharmacy and Medical Sciences
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Peter Howarth
GSK plc
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Pete Smith
Griffith University School of Medicine and Dentistry
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Raquel Alvarado
University of New South Wales
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Peter Earls
University of New South Wales
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Richard Harvey
University of New South Wales
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Amanda Cox
Griffith University School of Pharmacy and Medical Sciences
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Abstract

Background: There is limited understanding of the impact of anti-IL5 treatment on nasal polyp tissue biology in chronic rhinosinusitis with nasal polyps (CRSwNP). The aim of this study was to determine the effect of the nasal polyp tissue cellular proteome and transcriptome in response to six months of anti-IL5 treatment with mepolizumab in CRSwNP utilising high-plex spatial profiling. Methods: GeoMx™ Digital Spatial Profiling (DSP) of 80 proteins and 1,833 mRNA targets in the polyp stroma and of the whole transcriptome (18,815 mRNA targets) in polyp epithelia was undertaken on formalin-fixed paraffin embedded slides of sinonasal biopsies collected before and after 16 and 24 weeks of treatment with mepolizumab. Results: Anti-IL5 therapy with mepolizumab in patients with eosinophilic CRSwNP had significant tissue biological impact. Treatment-related changes in proteins within immune checkpoint inhibition, neutrophil degranulation and the innate immune system were key biological mechanisms 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 with treatment. Conclusions: Spatial profiling technology demonstrates that the effects of anti-IL5 treatment within nasal polyp tissue extend well beyond simple eosinophil reduction to broader regulation of innate and adaptive immune cells and in improving the epithelial barrier biology.
20 Oct 2024Submitted to Allergy
22 Oct 2024Submission Checks Completed
22 Oct 2024Assigned to Editor
22 Oct 2024Review(s) Completed, Editorial Evaluation Pending
23 Oct 2024Reviewer(s) Assigned