IL-33/IL1RL1 (ST2) signalling drives immune suppression in squamous intraepithelial hyperplasia.

: IL-33, an alarmin cytokine binding to IL1RL1 (ST2) receptor, plays a multifaceted role in cancer. Using an HPV16-E7 oncoprotein-mediated murine model of squamous intraepithelial hyperplasia, a pre-stage of squamous cell carcinoma (SCC), we characterised the interactions of hyperproliferative epithelial cells and immune cells regulated by IL-33 and IL1RL1. We show that basal epithelial cells in epithelial hyperplasia co-express IL-33 and genes involved in MHC class II antigen presentation and in epithelial stress response. Using spatial transcriptomics, we demonstrate that IL1RL1 + Foxp3 + Tregs are in close proximity to IL-33-expressing cells, in both the murine model and in human cervical intraepithelial neoplastic tissues. Cytoplasmic location of IL-33 is associated with its bioactivity, and we show that a subset of epithelial cells in epithelial hyperplasia contains high levels of cytoplasmic IL-33. Genetic deletion of the IL1RL1 gene led to partial rejection of HPV16-E7-expressing skin grafts, demonstrating that IL1RL1 plays a functional role in mediating immune suppression in epithelial hyperplasia. IL1RL1-deletion further led to a significant reduction in Tregs in epithelial hyperplasia. The IL1RL1 signalling pathway, therefore, represents a potential therapeutic target for intraepithelial hyperplasia and SCC.