Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Top
  • View PDF
  • Download citation information
  • Send a letter
  • Share this article
  • Terms of use
  • Standard abbreviations
  • Need Help? E-mail the JCI
  • Top
  • Abstract
  • Supplemental material
  • Version history
  • Article usage
  • Citations to this article

Advertisement

ResearchIn-Press PreviewImmunologyNeuroscience Free access | 10.1172/JCI139542

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

Padma Kadiyala,1 Stephen V. Carney,1 Jessica C. Gauss,1 Maria B. Garcia-Fabiani,1 Santiago Haase,1 Mahmoud S. Alghamri,1 Felipe J. Núñez,1 Yayuan Liu,2 Minzhi Yu,2 Ayman W. Taher,1 Fernando M. Nunez,1 Dan Li,2 Marta B. Edwards,1 Celina G. Kleer,3 Henry Appelman,4 Yilun Sun,5 Lili Zhao,6 James J. Moon,2 Anna Schwendeman,2 Pedro R. Lowenstein,1 and Maria G. Castro1

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 Kadiyala, 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 Carney, 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 Gauss, 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 Garcia-Fabiani, 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 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

Find articles by Núñez, 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 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 - More info

J Clin Invest. https://doi.org/10.1172/JCI139542.
Copyright © 2020, American Society for Clinical Investigation
Published December 17, 2020 - Version history
View PDF
Abstract

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.

Graphical Abstract
graphical abstract
Supplemental material

View

Version history
  • Version 1 (December 17, 2020): In-Press Preview

Article tools

  • View PDF
  • Download citation information
  • Send a letter
  • Share this article
  • Terms of use
  • Standard abbreviations
  • Need Help? E-mail the JCI

Metrics

  • Article usage
  • Citations to this article

Go to

  • Top
  • Abstract
  • Supplemental material
  • Version history
Advertisement
Advertisement
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts