دورية أكاديمية
Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity.
| العنوان: | Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity. |
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| المؤلفون: | Wu MJ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Kondo H; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Kammula AV; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Shi L; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Xiao Y; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Dhiab S; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Xu Q; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Slater CJ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Universite Paris-Saclay, Institut Gustave Roussy, INSERM U1015, Villejuif, France.; Servier Pharmaceuticals LLC, Boston, MA, USA., Avila OI; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Merritt J; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Kato H; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Kattel P; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Sussman J; Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Graduate Group in Genomics and Computational Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Gritti I; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Eccleston J; Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Sun Y; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA., Cho HM; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Olander K; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Katsuda T; Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Shi DD; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA., Savani MR; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, TX, USA., Smith BC; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Cleary JM, Mostoslavsky R; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Vijay V; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Kitagawa Y; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Wakimoto H; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Jenkins RW; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA., Yates KB; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Paik J; Department of Pathology and Laboratory Medicine, Sandra and Edward Meyer Cancer Center, Weill Medical College of Cornell University, New York, NY, USA., Tassinari A; Servier Pharmaceuticals LLC, Boston, MA, USA., Saatcioglu DH; Servier Pharmaceuticals LLC, Boston, MA, USA., Tron AE; Servier Pharmaceuticals LLC, Boston, MA, USA., Haas W; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Cahill D; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., McBrayer SK; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Manguso RT; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Bardeesy N; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. |
| المصدر: | Science (New York, N.Y.) [Science] 2024 Jul 12; Vol. 385 (6705), pp. eadl6173. Date of Electronic Publication: 2024 Jul 12. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Original Publication: New York, N.Y. : [s.n.] 1880- |
| مواضيع طبية MeSH: | Immunity, Innate*/genetics , Isocitrate Dehydrogenase*/genetics , Isocitrate Dehydrogenase*/metabolism , Neoplasms*/immunology , Neoplasms*/genetics , Immune Evasion*/genetics, Animals ; Humans ; Mice ; Cell Line, Tumor ; DNA/metabolism ; DNA Demethylation ; DNA Methylation ; DNA Transposable Elements ; Epigenesis, Genetic ; Glutarates/metabolism ; Mutation ; Nucleotidyltransferases/genetics ; Tumor Escape |
| مستخلص: | Isocitrate dehydrogenase 1 ( IDH1 ) is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of IDH1 -mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores antitumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1 -mutant solid tumors show selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (dsDNA) sensor CGAS , compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase (TE-RT) activates cGAS, triggering viral mimicry and stimulating antitumor immunity. In summary, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous RT activity to the mechanism of action of a US Food and Drug Administration-approved oncology drug. |
| التعليقات: | Comment in: Science. 2024 Jul 12;385(6705):140-142. doi: 10.1126/science.adq5196. (PMID: 38991086) |
| معلومات مُعتمدة: | K99 CA277576 United States CA NCI NIH HHS |
| المشرفين على المادة: | 2889-31-8 (alpha-hydroxyglutarate) EC 2.7.7.- (cGAS protein, mouse) 9007-49-2 (DNA) 0 (DNA Transposable Elements) 0 (Glutarates) EC 1.1.1.42. (IDH1 protein, human) EC 1.1.1.42 (Idh1 protein, mouse) EC 1.1.1.41 (Isocitrate Dehydrogenase) EC 2.7.7.- (Nucleotidyltransferases) |
| تواريخ الأحداث: | Date Created: 20240711 Date Completed: 20240711 Latest Revision: 20240723 |
| رمز التحديث: | 20240723 |
| DOI: | 10.1126/science.adl6173 |
| PMID: | 38991060 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1095-9203 |
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| DOI: | 10.1126/science.adl6173 |