Diet, Immune Responses and Liver Cancer

Abstract

Currently, therapeutic and preventive approaches across a variety of diseases have incorporated an immunological perspective. In particular, it is now well-established that the immune system modulates cancer growth. Likewise for the liver, there has been substantial interest in the role of the immune system in governing liver cancer behaviour and several immuno-modulatory approaches have been proposed. A large number of studies have also shown that nutrition and bile acid regulation, independently impact the development and progression of gastrointestinal cancers. While the immune-modulatory effects of excess intake of certain nutrients and bile salts in a few hepatobiliary diseases such as NASH and cholestasis have been reported, no study has explored this in the context of liver cancer. The aim of this work was to combine these views to elucidate the link between nutrition, the immune system and liver cancer. I investigated the role of diet and bile acids in liver cancer development and progression from an immune perspective using one of the most commonly used murine models of liver cancer that develops following the administration of diethylnitrosamine (DEN). We observed that short-term dietary manipulation with both sucrose and cholate rich diets enhanced liver tumour incidence in DEN-treated mice. Prolonged dietary manipulation exacerbated this pathology as DEN-treated mice fed sucrose or cholate enriched diets exhibited a significantly greater number of tumours and a larger total tumour volume compared to the control group receiving a standard chow diet. This was independent of obesity or glucose tolerance. Indeed, the long-term sucrose rich diet impaired hepatic and splenic anti-tumour immunity and promoted local and systemic pro-tumour immunity. Similarly, long-term cholate vi administration induced a potentially pro-tumour immune signature in the liver and impaired splenic anti-tumour immunity. The specific combination of sucrose and cholate with cholesterol (i.e., the atherogenic diet) induced a totally divergent liver pathology and gave rise to tumours that were smaller than those of the two former groups. The hepatic and systemic immune milieu in the atherogenic diet group was skewed toward a TH-1 phenotype which was in favour of immune-tolerance abrogation and HCC suppression. Overall, this study has highlighted the importance of the diet and the immune system in the context of liver cancer progression. I have shown that the immune phenotype is heavily altered by nutrition and that the effect of dietary manipulation on liver tumour development and progression is at least partially through hepatic and systemic immune alterations.