G-CSF secreted by mutant IDH1 glioma stem cells abolishes myeloid cell immunosuppression and enhances the efficacy of immunotherapy.

Autor: Alghamri MS; 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., McClellan BL; 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., Avvari RP; 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., Thalla R; 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., Carney S; 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., Hartlage CS; 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., Haase S; 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., Ventosa M; 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., Taher A; 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., Kamran N; 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., Zhang L; 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., Faisal SM; 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., Núñez FJ; 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., Garcia-Fabiani MB; 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., Al-Holou WN; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Orringer D; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Hervey-Jumper S; Department of Neurosurgery, University of California San Francisco, San Francisco, CA 94143, USA., Heth J; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Patil PG; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Eddy K; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Merajver SD; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Ulintz PJ; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Welch J; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Gao C; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Liu J; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Núñez G; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Hambardzumyan D; Department of Oncological Sciences, The Tisch Cancer Institute, and Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Lowenstein PR; 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., Castro MG; 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.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2021 Oct; Vol. 7 (40), pp. eabh3243. Date of Electronic Publication: 2021 Sep 29.
DOI: 10.1126/sciadv.abh3243
Abstrakt: 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.
Databáze: MEDLINE