The role of tissue-resident immune cells in PanIN to PDAC progression
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer deaths worldwide. PDAC is recalcitrant to current immunotherapies, largely due to local suppression of anti-tumour immunity. Tissue-resident group 2 innate lymphoid cells (ILC2) are emerging as important immune modulators of the cancer microenvironment, although their role in PDAC remains contentious with both pro- and anti-cancer roles having been described. In this thesis, I have characterised the role of ILC2 in early- and late-stage PDAC with specific focus on how ILC2 interact with stromal and immune components in the peri-tumour niche. In murine pre-clinical models of PDAC, ILC2 are seen to localise in the stromal-rich and immune modulatory tumour-margin. ILC2-deficient mice and PDAC TCGA ILC2-low patients demonstrated a substantial survival advantage that was proportional to PDAC immunogenicity, suggesting that ILC2 restrain adaptive anti-tumour immunity. ILC2, in collaboration with cancer associated fibroblasts (CAF), influenced the density and co-localisation of immune-suppressive regulatory T cells (Treg) with ‘stem like’ PD-1+TCF1+ CD8+ exhausted progenitor (TEP) cells at the tumour margin. Mechanistically, ILC2 influence the expression of chemo-attractants, including a recently identified cholesterol metabolite 7α,25-OHC, to which these Treg and CD8+ T cells migrate and localise. Hence, ILC2-mediated choreography of stromal-immune interactions influences anti-cancer immunity in PDAC. Pancreatic intraepithelial neoplasia (PanIN) are early malignant lesions that commonly give rise to PDAC. Using a combination of autochthonous mouse models, as well as orthotopic PanIN models, ILC2 are seen to expand and be activated in the pre-cancerous setting. ILC2 influenced the phenotype of local fibroblasts, and in collaboration they promoted the expansion of Treg with enhanced suppressive capacity. This led to CD8+ T cell exhaustion and in turn, the suppression of anti-cancer immunity in the PanIN niche. Thus, ILC2 promote PanIN to PDAC progression and the body of work in this thesis highlights therapeutic targets to better control PDAC and enhance patient outcome and prognosis from early- to late-stage diagnosis.
ILC2, pancreatic cancer, PanIN, Treg, CD8, immunology
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