Functions of mutant IDH in cholangiocarcinoma

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PROJECT SUMMARY Isocitrate dehydrogenase 1 is the most frequently mutated metabolic gene across all cancers. Among epithelial malignancies, IDH1 mutations are particularly common in cholangiocarcinoma, a deadly cancer of the liver bile ducts. These hot-spot mutations generate the oncometabolite, (R)-2-hydroxyglutarate, which inhibits - ketoglutarate-dependent enzymes, altering epigenetics and metabolism. While pharmacological inhibition of mutant IDH1 shows efficacy in cholangiocarcinoma, the effects are not durable, and there has been limited insight into the basis for response and resistance. Recently, by developing mIDH1-driven genetically engineered mouse models and utilizing patient samples and models, we demonstrated that mIDH1 causes tumor cells to evade attack by the immune system. We find that inhibitors of mutant IDH1 slow tumor growth by reverting this immune evasion phenotype, leading to sensitization to immune checkpoint blockade. A major mechanism of this evasion involves the (R)-2HG-mediated inactivation of the TET2 demethylase, which prevents the tumor cells from responding to interferon gamma produced by immune cells. The second mechanism involves limiting the recruitment and activity of cytotoxic T cells, although we have yet to fully elucidate the associated molecular basis. Based on our extensive new preliminary data, we hypothesize that IDH1-mediated control of cellular differentiation and of innate immune signaling are potential mediators of this T cell cross-talk. The present proposal will test this hypothesis and investigate the interplay between T cell recruitment and the IFN-g-TET2 program in IDH1 inhibitor response and eventual resistance. These studies will inform the improved treatment of cholangiocarcinoma and potentially the range of other cancer types harboring IDH mutations.