Matches in SemOpenAlex for { <https://semopenalex.org/work/W4223991457> ?p ?o ?g. }
- W4223991457 endingPage "835" @default.
- W4223991457 startingPage "812" @default.
- W4223991457 abstract "Abstract 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. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon γ (IFNγ) expression and promotes TET2-dependent induction of IFNγ response genes in tumor cells. CD8+ T-cell depletion or tumor cell–specific ablation of TET2 or IFNγ 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 IFNγ–TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy. Significance: Mutant IDH1 inhibition stimulates cytotoxic T-cell function and derepression of the DNA demethylating enzyme TET2, which is required for tumor cells to respond to IFNγ. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies. See related commentary by Zhu and Kwong, p. 604. This article is highlighted in the In This Issue feature, p. 587" @default.
- W4223991457 created "2022-04-19" @default.
- W4223991457 creator A5004618856 @default.
- W4223991457 creator A5007585092 @default.
- W4223991457 creator A5009519345 @default.
- W4223991457 creator A5011220872 @default.
- W4223991457 creator A5011327903 @default.
- W4223991457 creator A5021570234 @default.
- W4223991457 creator A5022155277 @default.
- W4223991457 creator A5026104619 @default.
- W4223991457 creator A5027338121 @default.
- W4223991457 creator A5033056679 @default.
- W4223991457 creator A5033651320 @default.
- W4223991457 creator A5035416678 @default.
- W4223991457 creator A5038972103 @default.
- W4223991457 creator A5044802816 @default.
- W4223991457 creator A5049849121 @default.
- W4223991457 creator A5050330697 @default.
- W4223991457 creator A5050811963 @default.
- W4223991457 creator A5054028672 @default.
- W4223991457 creator A5058709133 @default.
- W4223991457 creator A5061627885 @default.
- W4223991457 creator A5062062198 @default.
- W4223991457 creator A5064406116 @default.
- W4223991457 creator A5065926112 @default.
- W4223991457 creator A5070417140 @default.
- W4223991457 creator A5071621244 @default.
- W4223991457 creator A5076838821 @default.
- W4223991457 creator A5076895696 @default.
- W4223991457 creator A5079433380 @default.
- W4223991457 creator A5080484531 @default.
- W4223991457 creator A5082908624 @default.
- W4223991457 creator A5083455588 @default.
- W4223991457 creator A5084015325 @default.
- W4223991457 creator A5085634885 @default.
- W4223991457 date "2022-03-01" @default.
- W4223991457 modified "2023-10-15" @default.
- W4223991457 title "Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma" @default.
- W4223991457 cites W1984069598 @default.
- W4223991457 cites W1995675594 @default.
- W4223991457 cites W2008777301 @default.
- W4223991457 cites W2009550277 @default.
- W4223991457 cites W2011376261 @default.
- W4223991457 cites W2015755329 @default.
- W4223991457 cites W2051207198 @default.
- W4223991457 cites W2066640259 @default.
- W4223991457 cites W2078811578 @default.
- W4223991457 cites W2078972833 @default.
- W4223991457 cites W2080452140 @default.
- W4223991457 cites W2094851085 @default.
- W4223991457 cites W2096796171 @default.
- W4223991457 cites W2114843025 @default.
- W4223991457 cites W2120920194 @default.
- W4223991457 cites W2121080857 @default.
- W4223991457 cites W2123106337 @default.
- W4223991457 cites W2126817554 @default.
- W4223991457 cites W2130410032 @default.
- W4223991457 cites W2131860315 @default.
- W4223991457 cites W2132555177 @default.
- W4223991457 cites W2135030836 @default.
- W4223991457 cites W2142898716 @default.
- W4223991457 cites W2149441684 @default.
- W4223991457 cites W2154313451 @default.
- W4223991457 cites W2192221936 @default.
- W4223991457 cites W2195565943 @default.
- W4223991457 cites W2275249553 @default.
- W4223991457 cites W2324488473 @default.
- W4223991457 cites W2461331156 @default.
- W4223991457 cites W2496785181 @default.
- W4223991457 cites W2520340383 @default.
- W4223991457 cites W2537440061 @default.
- W4223991457 cites W2566555267 @default.
- W4223991457 cites W2585230893 @default.
- W4223991457 cites W2588385654 @default.
- W4223991457 cites W2594708898 @default.
- W4223991457 cites W2596261790 @default.
- W4223991457 cites W2596760231 @default.
- W4223991457 cites W2611222875 @default.
- W4223991457 cites W2612372140 @default.
- W4223991457 cites W2612431515 @default.
- W4223991457 cites W2755660258 @default.
- W4223991457 cites W2767343890 @default.
- W4223991457 cites W2771485688 @default.
- W4223991457 cites W2782192099 @default.
- W4223991457 cites W2800392236 @default.
- W4223991457 cites W2803357178 @default.
- W4223991457 cites W2806682325 @default.
- W4223991457 cites W2806800293 @default.
- W4223991457 cites W2810336146 @default.
- W4223991457 cites W2810919053 @default.
- W4223991457 cites W2878436114 @default.
- W4223991457 cites W2887976258 @default.
- W4223991457 cites W2890911268 @default.
- W4223991457 cites W2896518632 @default.
- W4223991457 cites W2899145148 @default.
- W4223991457 cites W2909014200 @default.
- W4223991457 cites W2909486828 @default.
- W4223991457 cites W2911108160 @default.