Group 2 innate lymphoid cells (ILC2) are important orchestrators of type 2 inflammation with established roles in anti-helminth immunity and allergic disease. More recent studies have shown both pro- and anti-tumourigenic functions, indicating our incomplete understanding of their role in cancer. Another emerging notion within the field is that ILC2 interactions with cells of mesenchymal origin, including fibroblasts, are critical for their functions in homeostasis and inflammatory states. Furthermore, immune niches enriched in fibroblasts and type 2 immune cells have recently been described in various homeostatic and disease contexts. Given the advancements in our appreciation of fibroblast heterogeneity in steady and perturbed states, as well as the importance of fibroblast contributions to pancreatic pathologies, in this thesis I characterised fibroblast and ILC2 populations in the pancreas and defined the mechanisms of their bi-directional communication in homeostatic, inflamed, and neoplastic states.

The majority of pancreatic ILC2s were localised together with a subset of Pi16⁺Ly6c1⁺Dpp4⁺Il33⁺ fibroblasts within an unappreciated interstitial niche beneath the submesothelial surface and within the interlobular septae of the exocrine pancreas. Computational and experimental evidence suggested that these Pi16⁺ fibroblasts serve as progenitors for parenchymal Col15a1⁺ fibroblasts that bear resemblance to pancreatic stellate cells. In homeostatic conditions, ILC2s were associated with increased fibroblast abundance; upon activation, ILC2s were found to promote proliferation of Pi16⁺ fibroblasts while restraining Col15a1⁺ fibroblast numbers. Mechanistic profiling using in vitro and in vivo models suggested that IL-13 and other ILC2-derived factors promoted fibroblast proliferation, while oncostatin M production by activated ILC2s might be responsible for inducing apoptosis in Col15a1⁺ fibroblasts.

This ILC2-dependent signalling axis was found to promote fibroblast progenitor proliferation in mouse models of caerulein-induced acute pancreatitis, potentially to restore fibroblast numbers after acute injury. I next investigated how ILC2-fibroblast signalling was affected in mouse models of pancreatic adenocarcinoma. In preneoplastic pancreatic lesions, ILC2 numbers were found to be substantially increased, with a dramatic local co-expansion of Dpp4⁺Ly6c1⁺ fibroblasts in the desmoplastic peritumoural stroma. Using orthotopic implantation models of pancreatic cancer, I demonstrated that the presence of ILC2s resulted in increased abundance of inflammatory cancer-associated fibroblasts (CAFs) that may promote tumour progression. Together, these data define a role for ILC2-fibroblast interactions for their mutual support in homeostatic conditions, that may be abnormally activated in pancreatic cancer.