أعرض في EDS

Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma

التفاصيل البيبلوغرافية
العنوان:	Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma
المؤلفون:	Emily Kessler, Rodrigo Saad-Berreta, Hongwu Zheng, Vikram Deshpande, Krishna S. Tummala, Brandon Nicolay, William Shen, Ramzi Adil, Meng-Ju Wu, Juan Dubrot, Lipika Goyal, Vajira Weeresekara, Amaya Pankaj, Mathias Heikenwalder, Tong Wang, Mirian Fernandez-Vaquero, María García-Beccaria, Ting-Yu Wei, Kira E Olander, Sebastien Ronseaux, Vindhya Vijay, Qibiao Wu, Yuanli Zhen, Christine Hudson, Nabeel Bardeesy, Lei Shi, Rahul M. Kohli, Meiqi Luo, Yi Sun, Russell W. Jenkins, Robert T. Manguso, Cristina R. Ferrone, Joshua Merritt
المصدر:	Cancer Discovery. 12:812-835
بيانات النشر:	American Association for Cancer Research (AACR), 2022.
سنة النشر:	2022
مصطلحات موضوعية:	T cell, Dioxygenases, Cholangiocarcinoma, Interferon-gamma, Mice, Immune system, Interferon, medicine, Animals, Humans, CTLA-4 Antigen, Receptor, biology, Chemistry, Isocitrate Dehydrogenase, Immune checkpoint, DNA-Binding Proteins, Bile Ducts, Intrahepatic, medicine.anatomical_structure, Isocitrate dehydrogenase, Bile Duct Neoplasms, Oncology, Mutation, Cancer research, biology.protein, Demethylase, CD8, medicine.drug
الوصف:	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
تدمد:	2159-8290 2159-8274
الوصول الحر:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f862d0e585b8159d6489f25b69e68d80Test https://doi.org/10.1158/2159-8290.cd-21-1077Test
رقم الانضمام:	edsair.doi.dedup.....f862d0e585b8159d6489f25b69e68d80
قاعدة البيانات:	OpenAIRE

ResultId	1
Header	edsair OpenAIRE edsair.doi.dedup.....f862d0e585b8159d6489f25b69e68d80 905 3 unknown 905.373779296875
PLink	https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&scope=site&db=edsair&AN=edsair.doi.dedup.....f862d0e585b8159d6489f25b69e68d80&custid=s6537998&authtype=sso
FullText	Array ( [Availability] => 0 )
Items	Array ( [Name] => Title [Label] => Title [Group] => Ti [Data] => Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma ) Array ( [Name] => Author [Label] => Authors [Group] => Au [Data] => <searchLink fieldCode="AR" term="%22Emily+Kessler%22">Emily Kessler</searchLink><br /><searchLink fieldCode="AR" term="%22Rodrigo+Saad-Berreta%22">Rodrigo Saad-Berreta</searchLink><br /><searchLink fieldCode="AR" term="%22Hongwu+Zheng%22">Hongwu Zheng</searchLink><br /><searchLink fieldCode="AR" term="%22Vikram+Deshpande%22">Vikram Deshpande</searchLink><br /><searchLink fieldCode="AR" term="%22Krishna+S%2E+Tummala%22">Krishna S. Tummala</searchLink><br /><searchLink fieldCode="AR" term="%22Brandon+Nicolay%22">Brandon Nicolay</searchLink><br /><searchLink fieldCode="AR" term="%22William+Shen%22">William Shen</searchLink><br /><searchLink fieldCode="AR" term="%22Ramzi+Adil%22">Ramzi Adil</searchLink><br /><searchLink fieldCode="AR" term="%22Meng-Ju+Wu%22">Meng-Ju Wu</searchLink><br /><searchLink fieldCode="AR" term="%22Juan+Dubrot%22">Juan Dubrot</searchLink><br /><searchLink fieldCode="AR" term="%22Lipika+Goyal%22">Lipika Goyal</searchLink><br /><searchLink fieldCode="AR" term="%22Vajira+Weeresekara%22">Vajira Weeresekara</searchLink><br /><searchLink fieldCode="AR" term="%22Amaya+Pankaj%22">Amaya Pankaj</searchLink><br /><searchLink fieldCode="AR" term="%22Mathias+Heikenwalder%22">Mathias Heikenwalder</searchLink><br /><searchLink fieldCode="AR" term="%22Tong+Wang%22">Tong Wang</searchLink><br /><searchLink fieldCode="AR" term="%22Mirian+Fernandez-Vaquero%22">Mirian Fernandez-Vaquero</searchLink><br /><searchLink fieldCode="AR" term="%22María+García-Beccaria%22">María García-Beccaria</searchLink><br /><searchLink fieldCode="AR" term="%22Ting-Yu+Wei%22">Ting-Yu Wei</searchLink><br /><searchLink fieldCode="AR" term="%22Kira+E+Olander%22">Kira E Olander</searchLink><br /><searchLink fieldCode="AR" term="%22Sebastien+Ronseaux%22">Sebastien Ronseaux</searchLink><br /><searchLink fieldCode="AR" term="%22Vindhya+Vijay%22">Vindhya Vijay</searchLink><br /><searchLink fieldCode="AR" term="%22Qibiao+Wu%22">Qibiao Wu</searchLink><br /><searchLink fieldCode="AR" term="%22Yuanli+Zhen%22">Yuanli Zhen</searchLink><br /><searchLink fieldCode="AR" term="%22Christine+Hudson%22">Christine Hudson</searchLink><br /><searchLink fieldCode="AR" term="%22Nabeel+Bardeesy%22">Nabeel Bardeesy</searchLink><br /><searchLink fieldCode="AR" term="%22Lei+Shi%22">Lei Shi</searchLink><br /><searchLink fieldCode="AR" term="%22Rahul+M%2E+Kohli%22">Rahul M. Kohli</searchLink><br /><searchLink fieldCode="AR" term="%22Meiqi+Luo%22">Meiqi Luo</searchLink><br /><searchLink fieldCode="AR" term="%22Yi+Sun%22">Yi Sun</searchLink><br /><searchLink fieldCode="AR" term="%22Russell+W%2E+Jenkins%22">Russell W. Jenkins</searchLink><br /><searchLink fieldCode="AR" term="%22Robert+T%2E+Manguso%22">Robert T. Manguso</searchLink><br /><searchLink fieldCode="AR" term="%22Cristina+R%2E+Ferrone%22">Cristina R. Ferrone</searchLink><br /><searchLink fieldCode="AR" term="%22Joshua+Merritt%22">Joshua Merritt</searchLink> ) Array ( [Name] => TitleSource [Label] => Source [Group] => Src [Data] => <i>Cancer Discovery</i>. 12:812-835 ) Array ( [Name] => Publisher [Label] => Publisher Information [Group] => PubInfo [Data] => American Association for Cancer Research (AACR), 2022. ) Array ( [Name] => DatePubCY [Label] => Publication Year [Group] => Date [Data] => 2022 ) Array ( [Name] => Subject [Label] => Subject Terms [Group] => Su [Data] => <searchLink fieldCode="DE" term="%22T+cell%22">T cell</searchLink><br /><searchLink fieldCode="DE" term="%22Dioxygenases%22">Dioxygenases</searchLink><br /><searchLink fieldCode="DE" term="%22Cholangiocarcinoma%22">Cholangiocarcinoma</searchLink><br /><searchLink fieldCode="DE" term="%22Interferon-gamma%22">Interferon-gamma</searchLink><br /><searchLink fieldCode="DE" term="%22Mice%22">Mice</searchLink><br /><searchLink fieldCode="DE" term="%22Immune+system%22">Immune system</searchLink><br /><searchLink fieldCode="DE" term="%22Interferon%22">Interferon</searchLink><br /><searchLink fieldCode="DE" term="%22medicine%22">medicine</searchLink><br /><searchLink fieldCode="DE" term="%22Animals%22">Animals</searchLink><br /><searchLink fieldCode="DE" term="%22Humans%22">Humans</searchLink><br /><searchLink fieldCode="DE" term="%22CTLA-4+Antigen%22">CTLA-4 Antigen</searchLink><br /><searchLink fieldCode="DE" term="%22Receptor%22">Receptor</searchLink><br /><searchLink fieldCode="DE" term="%22biology%22">biology</searchLink><br /><searchLink fieldCode="DE" term="%22Chemistry%22">Chemistry</searchLink><br /><searchLink fieldCode="DE" term="%22Isocitrate+Dehydrogenase%22">Isocitrate Dehydrogenase</searchLink><br /><searchLink fieldCode="DE" term="%22Immune+checkpoint%22">Immune checkpoint</searchLink><br /><searchLink fieldCode="DE" term="%22DNA-Binding+Proteins%22">DNA-Binding Proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Bile+Ducts%2C+Intrahepatic%22">Bile Ducts, Intrahepatic</searchLink><br /><searchLink fieldCode="DE" term="%22medicine%2Eanatomical%5Fstructure%22">medicine.anatomical_structure</searchLink><br /><searchLink fieldCode="DE" term="%22Isocitrate+dehydrogenase%22">Isocitrate dehydrogenase</searchLink><br /><searchLink fieldCode="DE" term="%22Bile+Duct+Neoplasms%22">Bile Duct Neoplasms</searchLink><br /><searchLink fieldCode="DE" term="%22Oncology%22">Oncology</searchLink><br /><searchLink fieldCode="DE" term="%22Mutation%22">Mutation</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+research%22">Cancer research</searchLink><br /><searchLink fieldCode="DE" term="%22biology%2Eprotein%22">biology.protein</searchLink><br /><searchLink fieldCode="DE" term="%22Demethylase%22">Demethylase</searchLink><br /><searchLink fieldCode="DE" term="%22CD8%22">CD8</searchLink><br /><searchLink fieldCode="DE" term="%22medicine%2Edrug%22">medicine.drug</searchLink> ) Array ( [Name] => Abstract [Label] => Description [Group] => Ab [Data] => 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 ) Array ( [Name] => ISSN [Label] => ISSN [Group] => ISSN [Data] => 2159-8290<br />2159-8274 ) Array ( [Name] => URL [Label] => Access URL [Group] => URL [Data] => <link linkTarget="URL" linkTerm="https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f862d0e585b8159d6489f25b69e68d80" linkWindow="_blank">https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f862d0e585b8159d6489f25b69e68d80</link><br /><link linkTarget="URL" linkTerm="https://doi.org/10.1158/2159-8290.cd-21-1077" linkWindow="_blank">https://doi.org/10.1158/2159-8290.cd-21-1077</link> ) Array ( [Name] => AN [Label] => Accession Number [Group] => ID [Data] => edsair.doi.dedup.....f862d0e585b8159d6489f25b69e68d80 )
RecordInfo	Array ( [BibEntity] => Array ( [Languages] => Array ( [0] => Array ( [Text] => Undetermined ) ) [PhysicalDescription] => Array ( [Pagination] => Array ( [PageCount] => 24 [StartPage] => 812 ) ) [Subjects] => Array ( [0] => Array ( [SubjectFull] => T cell [Type] => general ) [1] => Array ( [SubjectFull] => Dioxygenases [Type] => general ) [2] => Array ( [SubjectFull] => Cholangiocarcinoma [Type] => general ) [3] => Array ( [SubjectFull] => Interferon-gamma [Type] => general ) [4] => Array ( [SubjectFull] => Mice [Type] => general ) [5] => Array ( [SubjectFull] => Immune system [Type] => general ) [6] => Array ( [SubjectFull] => Interferon [Type] => general ) [7] => Array ( [SubjectFull] => medicine [Type] => general ) [8] => Array ( [SubjectFull] => Animals [Type] => general ) [9] => Array ( [SubjectFull] => Humans [Type] => general ) [10] => Array ( [SubjectFull] => CTLA-4 Antigen [Type] => general ) [11] => Array ( [SubjectFull] => Receptor [Type] => general ) [12] => Array ( [SubjectFull] => biology [Type] => general ) [13] => Array ( [SubjectFull] => Chemistry [Type] => general ) [14] => Array ( [SubjectFull] => Isocitrate Dehydrogenase [Type] => general ) [15] => Array ( [SubjectFull] => Immune checkpoint [Type] => general ) [16] => Array ( [SubjectFull] => DNA-Binding Proteins [Type] => general ) [17] => Array ( [SubjectFull] => Bile Ducts, Intrahepatic [Type] => general ) [18] => Array ( [SubjectFull] => medicine.anatomical_structure [Type] => general ) [19] => Array ( [SubjectFull] => Isocitrate dehydrogenase [Type] => general ) [20] => Array ( [SubjectFull] => Bile Duct Neoplasms [Type] => general ) [21] => Array ( [SubjectFull] => Oncology [Type] => general ) [22] => Array ( [SubjectFull] => Mutation [Type] => general ) [23] => Array ( [SubjectFull] => Cancer research [Type] => general ) [24] => Array ( [SubjectFull] => biology.protein [Type] => general ) [25] => Array ( [SubjectFull] => Demethylase [Type] => general ) [26] => Array ( [SubjectFull] => CD8 [Type] => general ) [27] => Array ( [SubjectFull] => medicine.drug [Type] => general ) ) [Titles] => Array ( [0] => Array ( [TitleFull] => Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma [Type] => main ) ) ) [BibRelationships] => Array ( [HasContributorRelationships] => Array ( [0] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Emily Kessler ) ) ) [1] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Rodrigo Saad-Berreta ) ) ) [2] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Hongwu Zheng ) ) ) [3] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Vikram Deshpande ) ) ) [4] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Krishna S. Tummala ) ) ) [5] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Brandon Nicolay ) ) ) [6] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => William Shen ) ) ) [7] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Ramzi Adil ) ) ) [8] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Meng-Ju Wu ) ) ) [9] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Juan Dubrot ) ) ) [10] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Lipika Goyal ) ) ) [11] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Vajira Weeresekara ) ) ) [12] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Amaya Pankaj ) ) ) [13] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Mathias Heikenwalder ) ) ) [14] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Tong Wang ) ) ) [15] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Mirian Fernandez-Vaquero ) ) ) [16] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => María García-Beccaria ) ) ) [17] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Ting-Yu Wei ) ) ) [18] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Kira E Olander ) ) ) [19] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Sebastien Ronseaux ) ) ) [20] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Vindhya Vijay ) ) ) [21] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Qibiao Wu ) ) ) [22] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Yuanli Zhen ) ) ) [23] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Christine Hudson ) ) ) [24] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Nabeel Bardeesy ) ) ) [25] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Lei Shi ) ) ) [26] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Rahul M. Kohli ) ) ) [27] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Meiqi Luo ) ) ) [28] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Yi Sun ) ) ) [29] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Russell W. Jenkins ) ) ) [30] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Robert T. Manguso ) ) ) [31] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Cristina R. Ferrone ) ) ) [32] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Joshua Merritt ) ) ) ) [IsPartOfRelationships] => Array ( [0] => Array ( [BibEntity] => Array ( [Dates] => Array ( [0] => Array ( [D] => 01 [M] => 03 [Type] => published [Y] => 2022 ) ) [Identifiers] => Array ( [0] => Array ( [Type] => issn-print [Value] => 21598290 ) [1] => Array ( [Type] => issn-print [Value] => 21598274 ) [2] => Array ( [Type] => issn-locals [Value] => edsair ) ) [Numbering] => Array ( [0] => Array ( [Type] => volume [Value] => 12 ) ) [Titles] => Array ( [0] => Array ( [TitleFull] => Cancer Discovery [Type] => main ) ) ) ) ) ) )
IllustrationInfo