Mutant-IDH inhibits Interferon-TET2 signaling to promote immunoevasion and tumor maintenance in cholangiocarcinoma

• Published in: Cancer discovery Vol. 12; no. 3; pp. 812 - 835
• Main Authors: Wu, Meng-Ju, Shi, Lei, Dubrot, Juan, Merritt, Joshua, Vijay, Vindhya, Wei, Ting-Yu, Kessler, Emily, Olander, Kira E., Adil, Ramzi, Pankaj, Amaya, Tummala, Krishna Seshu, Weeresekara, Vajira, Zhen, Yuanli, Wu, Qibiao, Luo, Meiqi, Shen, William, García-Beccaria, María, Fernández-Vaquero, Mirian, Hudson, Christine, Ronseaux, Sebastien, Sun, Yi, Saad-Berreta, Rodrigo, Jenkins, Russell W., Wang, Tong, Heikenwälder, Mathias, Ferrone, Cristina R., Goyal, Lipika, Nicolay, Brandon, Deshpande, Vikram, Kohli, Rahul M., Zheng, Hongwu, Manguso, Robert T., Bardeesy, Nabeel
• Format: Journal Article
• Language: English
• Published: 01.03.2022
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-21-1077

Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate-dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show 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-γ expression and promotes TET2-dependent induction of IFN-γ response genes in tumor cells. CD8 + T cell depletion or tumor cell-specific ablation of TET2 or Interferon-gamma receptor 1 causes treatment resistance. Whereas immune checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFN-γ-TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for harnessing these inhibitors therapeutically.