The role of tissue-resident immune cells in PanIN to PDAC progression
type: CreativeWork
description: 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 th…
abstract: 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 th…
author: Simpson, Charlotte
language: eng
keywords: ILC2, pancreatic cancer, PanIN, Treg, CD8, immunology
license: https://www.repository.cam.ac.uk/bitstreams/b380d527-f444-4150-9469-d35fa5a3ff40/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2025-09-24
date modified: 2026-07-24T01:33:13Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.126432