IL-33/IL1RL1 (ST2) signalling drives immune suppression in HPV-mediated epithelial hyperplasia

ABSTRACT: Interleukin 33 (IL-33), an alarmin cytokine binding to IL1RL1 (ST2) receptor, plays a pleiotropic and controversial role in cancer. Using a human papillomavirus (HPV) E7 oncoprotein-mediated murine model of cutaneous epithelial hyperplasia, we systematically characterised the interactions of epithelial cells and immune cells regulated by IL-33 and IL1RL1. Integration of single-cell RNA sequencing and flow cytometry data revealed that hyperplastic skin contains a unique basal epithelial cell phenotype expressing IL-33, and increased numbers of IL1RL1+Foxp3+ regulatory T cells (Tregs) compared to normal skin. Using spatial transcriptomics, we demonstrate that IL1RL1+Foxp3+Tregs were in close proximity to IL-33-expressing cells. The translocation of IL-33 from the nucleus to the cytoplasm is associated with its bioactivity, and we show that IL-33 protein accumulates in the cytoplasm in epithelial cells of hyperplastic skin, compared to nucleic location in normal epithelium. These results imply that the nuclear release of IL-33 may lead to the recruitment and activation of IL1RL1+Foxp3+Tregs to mediate immune suppression. To test the biological relevance of IL1RL1-signalling in hyperplastic skin, we used a skin graft model where the HPV E7 oncoprotein-mediated hyperplastic skin is tolerated when grafted to an immunocompetent recipient mouse. Ablation of the IL1RL1 gene from HPV-mediated hyperplastic skin and the graft host led to partial rejection of skin grafts, demonstrating that IL1RL1 plays a vital role in mediating immune suppression in this model. The IL1RL1 signalling pathway, therefore, represents a potential therapeutic target for epithelial cancer treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE297947 | GEO | 2026/09/23

REPOSITORIES: GEO