VitD_CancerImmunity: Vitamin D and Bile Acid Metabolic Control of Cancer Immunity

Diet plays a central role in the development and function of immune cells and has been shown to affect immune responses against pathogens, as well as in autoimmunity and cancer. Understanding how nutritional components affect immune processes could be highly beneficial, considering the cost-effectiveness and applicability of dietary supplementation. Diet is also a major regulator of the gut microbiota, with multiple consequences on host immunity. Recent work in the lab has established a protective role for dietary vitamin D in cancer using transplantable tumour mouse models. Remarkably, this phenomenon was found to be both immune and microbiota dependent. While the effect of vitamin D on immune cell function has been explored for the past three decades, it is not yet clear how vitamin D shapes host immunity in cancer. Interestingly, vitamin D metabolism involves enzymes that are also key in bile acid metabolism, and bile acids can bind and activate the vitamin D receptor in the intestine. Nevertheless, whether and how the vitamin D receptor modulates inflammation via bile acids remains largely unknown and is one of the key knowledge gaps in the field. In this proposed work, mouse models of increased vitamin D bioavailability, as well as diet manipulation together with a novel metabolomics approach will be used to unravel the mechanism by which vitamin D shapes the microbiota and supports host immunity. Cellular characterisation and metabolomic profiling of bile fluid will delineate novel players in the underlying mechanism of vitamin D immune protection in cancer. In parallel, I will examine the immune-modulatory effects of bile acids on the immune system and its role in cancer progression by targeting primary and secondary bile acid signalling pathways. Altogether, the work proposed here will contribute to the fundamental understanding of the roles of vitamin D and bile acids in immune cell function and may open new avenues in the development of cancer therapies.