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ResearchIn-Press PreviewImmunologyNeuroscience Free access | 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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Garcia-Fabiani, M.
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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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Alghamri, M.
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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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Yu, M.
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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
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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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Sun, Y.
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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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Moon, J.
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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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Schwendeman, A.
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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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Lowenstein, P.
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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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Published December 17, 2020 - More info
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.