Tertiary lymphoid structures in chronic rhinosinusitis with nasal polyps

About This Grant

PROJECT SUMMARY Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) is a debilitating condition characterized by intense type 2 inflammation of the paranasal sinus mucosa. A subset of eCRSwNP, including many patients with comorbid asthma and aspirin-exacerbation, can be particularly recalcitrant to medical and surgical treatment. Type 2 cytokines derived from innate and adaptive immune cells are responsible for most of the epithelial pathologic features in eCRSwNP. Dupilumab, a human monoclonal antibody to the IL-4 receptor alpha subunit, has been approved for use in eCRSwNP since 2019. The effectiveness of dupilumab for nasal polyps strongly implicates IL-4/IL-13 signaling as critical to CRSwNP pathogenesis, but the mechanism of disease recidivism when the antibody therapy is discontinued remains unknown. In this proposal, our central hypothesis is that a chronic type 2 inflammatory environment in eCRSwNP results from ongoing expression of IL-4 and IL-13 by CD4+ resident memory T cells (Trm), arising locally from memory-like Th2 progenitors. This premise is supported by evidence from flow cytometry and single cell RNA sequencing studies. At this time, the spatial location of these cells in polyp tissue has not been demonstrated. We hypothesize that while the clinical features of the eCRSwNP derive from the effects of IL-4/IL-13 receptor signaling on the epithelium, the ultimate basis of eCRSwNP resides in the ongoing dysregulated expression of type 2 cytokines by T cell populations residing in tertiary lymphoid structures. In aim 1, we will use spatial proteomic and transcriptomic methods to identify the IL-13-producing cells in their cellular neighborhoods, characterizing the cell types contributing to tertiary lymphoid structures and the cell-cell interactions that may provide upstream signals driving the disease. In aim 2, we propose to leverage the opportunity provided by patients receiving dupilumab therapy to gain further insight into upstream pathways though a transcriptomic approach. We will investigate differential gene expression within TLSs in the microenvironment of IL-13-producing Trms, identifying networks of stromal and innate immune cell populations driving IL-13 production under dupilumab treatment. In total, these studies will significantly advance current knowledge about type 2 inflammation in the nasal mucosa and will create an opportunity to develop innovative and potentially more durable therapies for eCRSwNP.