Inhibition of 2-Hydroxyglutarate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity in Mice

Padma Kadiyala; Stephen V. Carney; Jessica C. Gauss; Maria B. Garcia-Fabiani; Santiago Haase; Mahmoud S. Alghamri; Felipe J. Núñez; Yayuan Liu; Minzhi Yu; Ayman W. Taher; Fernando M. Nunez; Dan Li; Marta B. Edwards; Celina G. Kleer; Henry Appelman; Yilun Sun; Lili Zhao; James J. Moon; Anna Schwendeman; Pedro R. Lowenstein; Maria G. Castro

doi:10.1172/JCI139542

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Haase, S. in: JCI | PubMed | Google Scholar

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Alghamri, M. in: JCI | PubMed | Google Scholar |

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Liu, Y. in: JCI | PubMed | Google Scholar

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Yu, M. in: JCI | PubMed | Google Scholar |

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Taher, A. in: JCI | PubMed | Google Scholar

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Nunez, F. in: JCI | PubMed | Google Scholar

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Li, D. in: JCI | PubMed | Google Scholar

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Edwards, M. in: JCI | PubMed | Google Scholar

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Kleer, C. in: JCI | PubMed | Google Scholar

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Appelman, H. in: JCI | PubMed | Google Scholar

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Sun, Y. in: JCI | PubMed | Google Scholar |

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Zhao, L. in: JCI | PubMed | Google Scholar

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Moon, J. in: JCI | PubMed | Google Scholar |

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Schwendeman, A. in: JCI | PubMed | Google Scholar |

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Lowenstein, P. in: JCI | PubMed | Google Scholar |

¹Department of Neurosurgery, The University of Michigan Medical School, Ann Arbor, United States of America

²Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Pathology, University of Michigan, Ann Arbor, United States of America

⁵Department of Radiation Oncology, University of Michigan, Ann Arbor, United States of America

⁶Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Castro, M. in: JCI | PubMed | Google Scholar |

Published December 17, 2020 - Version history

Mutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into two molecular subgroups: (i) 1p/19q co-deletion/TERT-promoter mutations or (ii) inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work, focuses on gliomas’ subtype harboring mIDH1, TP53 and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of D-2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma bearing mice. Also, D-2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to D-2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in wild-type-IDH1 gliomas. Thus, we combined D-2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint-blockade and observed complete tumor regression in 60% of mIDH1 glioma bearing mice. This combination strategy reduced T-cell exhaustion and favored the generation of memory CD8⁺ T-cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data supports the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients.

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Inhibition of 2-Hydroxyglutarate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity in Mice

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Inhibition of 2-Hydroxyglutarate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity in Mice

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