Tryptophan-derived oncometabolites as novel mediators of cancer immune evasion

PROJECT SUMMARY Liver cancer incidence is rising globally, with an overall survival rate of about 20%. Developing new therapeutic strategies is therefore critical to improve treatment response and increase survival. Our lab has identified a novel metabolic vulnerability in liver cancer which could pave the way for new mechanisms of therapy. Starving tumors of the essential amino acid tryptophan (Trp) completely abrogates liver cancer growth in genetically engineered mouse models as well as syngeneic xenografts. Importantly, the vast majority of bodily Trp is metabolized and not used for protein synthesis. Therefore, we broadly tested adding back various Trp metabolites to identify those that were critical for tumor growth. We discovered that the novel oncometabolite indole-3-pyruvate (I3P) is the only downstream product of Trp capable of rescuing liver cancer growth. However, the growth-promoting effects of I3P are significantly stronger in vivo than in vitro, suggesting that it has a non cell-autonomous mechanism of action. I surveyed multiple different immune cell types relevant to the liver cancer microenvironment and found that I3P may play a critical role in modulating macrophage polarization. My studies will therefore focus on defining the role of I3P-mediated macrophage phenotypes in the immune response to liver cancer.