Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. By performing experiments in mice, it was shown that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate-mediated mechanisms – suppression of CD8+ T cell activity and tumor cell-autonomous inactivation of TET2 DNA demethylase. Pharmacological mIDH1 inhibition stimulates CD8+ T cell recruitment and IFN-y expression and promotes TET2-dependent induction of IFN-y response genes in tumor cells, suggesting a novel immunotherapy strategy for mIDH1 mutant cholangiocarcinomas.

(Wu, M. J., et al. – Cancer Discov., November 2021)

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