WIME: WNT-mediated immune evasion in intestinal homeostasis, regeneration and cancer

WNT signalling plays a critical role in normal in WNT signalling plays a critical role in normal intestinal homeostasis, regeneration and tumorigenesis. WNT is required for intestinal stem cell maintenance and injury-induced regeneration, while aberrant WNT activation causes cancer. Specifically, APC-truncating mutation are detected in ~80% of colorectal cancer (CRC), leading to hyperactivation of WNT signalling. Despite decades of research, targeting WNT signalling remains challenging due to on-target toxicity in stem cell compartments. Targeting WNT in CRC remains an unmet need. Immune checkpoint inhibition (ICI) shows remarkable responses in solid cancers such as melanoma. However, the majority of CRC patients with high WNT signature do not respond to current ICI strategies. Genomic analysis of the clinical data shows that the "T cell-inflamed" phenotype and WNT-low signature are the two strongest predictors of ICI response in multiple cancer types, suggesting a link between the two. Understanding the underlying biological processes appears fundamental to the development of immunotherapies and will benefit a large proportion of patients with WNT-activated tumour.

Our preliminary data show that WNT activation causes cytotoxic T cell (CTL) exclusion not only in CRC, but also in normal WNT-high intestinal crypts and in WNT-dependent irradiation-induced regeneration, suggesting that the role of WNT signalling in subverting immune responses is a physiological mechanism, highjacked by cancers. We propose a unique approach to study the mechanisms underlying WNT activation and the associated immunosuppression in normal intestine, regeneration and cancer. These insights will guide the development of tumour-specific therapies to sensitise ICI response in WNT-activated CRCs and other cancers with minimal toxicity. Our extensive expertise in WNT signalling, intestinal stem cell, CRC and organoid research will place us in a unique position to study WNT-mediated immune evasion.