Evaluating the function and the therapeutic potential of IFN-λ in intestinal carcinogenesis

Colorectal cancer is the third most common malignancy and the fourth leading cause of cancerrelated
deaths in the world, and its burden is expected to increase to more than 1,1 million deaths
per year by 2030. Better understanding of the carcinogenesis mechanisms is needed to improve
treatment strategies. Type I interferons (IFNs) exert diverse roles in the immune system and harbour
cytotoxic and anti-proliferative functions, which together confer anti-cancer properties that are
used in the clinic. However, type I IFN treatment efficiency is poor because of its pronounced sideeffects.
We hypothesize that the similar type III IFN-λ is a superior treatment, because its receptor
IFN-λR1 is expressed mainly on intestinal epithelial cells (IECs), suggesting that anti-cancer therapy
using IFN-λ may display a more favourable potency/side effect ratio than type I IFNs. We have data
showing that IFN-λR1-/- mice display enhanced colon tumour growth, indeed supporting a beneficial
role for IFN-λ in intestinal cancer. Therefore, we want to reveal the IEC-specific role of endogenous
IFN-λ signalling as well as the therapeutic potential of using IFN-λ in mouse models of intestinal
tumorigenesis. Moreover, we will investigate the underlying molecular mechanisms using both
murine and human primary intestinal epithelial cultures. This straight-forward project will aid in
fundamentally understanding intestinal carcinogenesis and will evaluate the use of IFN-λ for its
treatment.