Alghamri Mahmoud S, McClellan Brandon L, Avvari Ruthvik P, Thalla Rohit, Carney Stephen, Hartlage Carson S, Haase Santiago, Ventosa Maria, Taher Ayman, Kamran Neha, Zhang Li, Faisal Syed Mohd, Núñez Felipe J, Garcia-Fabiani María Belén, Al-Holou Wajd N, Orringer Daniel, Hervey-Jumper Shawn, Heth Jason, Patil Parag G, Eddy Karen, Merajver Sofia D, Ulintz Peter J, Welch Joshua, Gao Chao, Liu Jialin, Núñez Gabriel, Hambardzumyan Dolores, Lowenstein Pedro R, Castro Maria G
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.
Sci Adv. 2021 Oct;7(40):eabh3243. doi: 10.1126/sciadv.abh3243. Epub 2021 Sep 29.
Mutant isocitrate-dehydrogenase 1 () 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 gliomas, due to the reprogramming of the myeloid cells’ compartment infiltrating the tumor microenvironment (TME). We uncovered that the immature myeloid cells infiltrating the TME are mainly nonsuppressive neutrophils and preneutrophils. Myeloid cell reprogramming was triggered by granulocyte colony-stimulating factor (G-CSF) secreted by glioma stem/progenitor-like cells. Blocking G-CSF in 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 glioma TME and enhancing the efficacy of immune-stimulatory gene therapy.
突变型异柠檬酸脱氢酶1（）合成致癌代谢物2-羟基戊二酸（2HG），后者通过抑制DNA和组蛋白去甲基化酶引发胶质瘤细胞转录组的表观遗传重编程。我们发现，免疫刺激基因疗法（TK/Flt3L）在胶质瘤中的疗效得到增强，这是由于浸润肿瘤微环境（TME）的髓系细胞区室发生了重编程。我们发现，浸润TME的未成熟髓系细胞主要是无抑制作用的中性粒细胞和前中性粒细胞。髓系细胞重编程由胶质瘤干细胞/祖细胞样细胞分泌的粒细胞集落刺激因子（G-CSF）触发。在荷胶质瘤小鼠中阻断G-CSF可恢复肿瘤浸润髓系细胞的抑制潜能，加速肿瘤进展。我们证明，G-CSF可重编程骨髓粒细胞生成，导致胶质瘤TME内产生无抑制作用的髓系细胞，并增强免疫刺激基因疗法的疗效。
