Mutations in isocitrate dehydrogenase 1 (mIDH1) leading to DNA hypermethylation are common in clinical gliomas. Using mouse models, Alghamri et al. showed that mIDH1 gliomas are more responsive to immune-stimulatory gene therapy than wild-type (wtIDH1) gliomas. mIDH1 reprograms the suppressive TME myeloid compartment from immunosuppressive to mainly non-suppressive neutrophils and pre-neutrophils. This process is mediated by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem/progenitor-like cells. In TCGA data, G-CSF expression was associated with favorable outcomes only in mIDH1 gliomas.
Contributed by Margot O’Toole
ABSTRACT: Mutant isocitrate-dehydrogenase 1 (mIDH1) synthesizes the oncometabolite 2-hydroxyglutarate (2HG), which elicits epigenetic reprogramming of the glioma cells’ transcriptome by inhibiting DNA and histone demethylases. We show that the efficacy of immune-stimulatory gene therapy (TK/Flt3L) is enhanced in mIDH1 gliomas, due to the reprogramming of the myeloid cells’ compartment infiltrating the tumor microenvironment (TME). We uncovered that the immature myeloid cells infiltrating the mIDH1 TME are mainly nonsuppressive neutrophils and preneutrophils. Myeloid cell reprogramming was triggered by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem/progenitor-like cells. Blocking G-CSF in mIDH1 glioma–bearing mice restores the inhibitory potential of the tumor-infiltrating myeloid cells, accelerating tumor progression. We demonstrate that G-CSF reprograms bone marrow granulopoiesis, resulting in noninhibitory myeloid cells within mIDH1 glioma TME and enhancing the efficacy of immune-stimulatory gene therapy
Author Info: (1) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School
Author Info: (1) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (2) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (3) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (4) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (5) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (6) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (7) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (8) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (9) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (10) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (11) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (12) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (13) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (14) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (15) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (16) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (17) Department of Neurosurgery, University of California San Francisco, San Francisco, CA 94143, USA. (18) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (19) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (20) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (21) Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (22) Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (23) Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (24) Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (25) Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (26) Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (27) Department of Oncological Sciences, The Tisch Cancer Institute, and Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (28) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. (29) Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
