Investigating the roles of IL-25, IL-33 and ILC2s in APC-mutation-mediated colorectal cancer
Interleukin-25 (IL-25) and group 2 innate lymphoid cells (ILC2s) play critical roles in the host immune defense against intestinal parasitic helminth infections, through orchestrating the protective type 2 immune response, eliciting pathogen clearance, and promoting tissue repair. However, IL-25 and ILC2s have also been associated with inappropriate allergic reactions and autoimmune diseases, while their roles in immune responses to cancer are more poorly understood. Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, the majority of which are driven by loss-of-function mutations in the Adenomatous Polyposis Coli (APC) tumour suppressor gene, and are largely refractory to current cancer immunotherapies. As presented in this thesis, examination of cancer gene expression profiles from CRC patients in large, publicly available online databases indicated that increased tumour IL25 (but not IL33) expression is associated with reduced patient survival. Furthermore, analysis of human CRC patient biopsies, identified that IL-25R+ ILC2s are enriched in tumours, and negatively correlate with T helper 1 (Th1) and CD8+ T cells, indicative of impaired anti-tumour immunity. The hypothesis that IL-25 and ILC2s are pro-tumorigenic was tested using the Apc1322T/+ mouse model of APC-mutation-mediated spontaneous CRC. Strikingly, genetic ablation of IL-25 virtually doubled life-expectancy in Apc1322T/+ mice. Mechanistically, IL-25-activated ILC2s create an innate cancer-permissive immune-microenvironment through sustaining myeloid-derived suppressor cells (MDSCs) via IL-4 and IL-13, thereby suppressing anti-tumour interferon-γ (IFNγ), Th1 and CD8+ T cell-mediated immunity. Notably, therapeutic blockade of IL-25-signalling decreased tumour ILC2s, MDSCs and cancer burden, while enhancing anti-tumour IFNγ and adaptive T cell immunity. Overall, the IL-25-ILC2 axis is a previously uncharacterised pathway in promoting intestinal tumorigenesis, and these results suggest that IL-25-signalling blockade may be beneficial against CRC.