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

被引：60

作者：

Alghamri, Mahmoud S. ^{[1
,2
]}

McClellan, Brandon L. ^{[1
,2
,3
]}

Avvari, Ruthvik P. ^{[1
,2
]}

Thalla, Rohit ^{[1
,2
]}

Carney, Stephen ^{[1
,2
]}

Hartlage, Margaret S. ^{[1
,2
]}

Haase, Santiago ^{[1
,2
]}

Ventosa, Maria ^{[1
,2
]}

Taher, Ayman ^{[1
,2
]}

Kamran, Neha ^{[1
,2
]}

Zhang, Li ^{[1
,2
]}

Faisal, Syed Mohd ^{[1
,2
]}

Nunez, Felipe J. ^{[1
,2
,11
]}

Garcia-Fabiani, Maria Belen ^{[1
,2
]}

Al-Holou, Wajd N. ^{[1
]}

Orringer, Daniel ^{[1
,12
]}

Hervey-Jumper, Shawn ^{[4
]}

Heth, Jason ^{[1
]}

Patil, Parag G. ^{[1
]}

Eddy, Karen ^{[1
]}

Merajver, Sofia D. ^{[5
]}

Ulintz, Peter J. ^{[5
,13
]}

Welch, Joshua ^{[6
]}

Gao, Chao ^{[6
]}

Liu, Jialin ^{[6
]}

Nunez, Gabriel ^{[7
]}

Hambardzumyan, Dolores ^{[8
,9
]}

Lowenstein, Pedro R. ^{[1
,2
,10
]}

Castro, Maria G. ^{[1
,2
,10
]}

机构：

[1] Univ Michigan, Dept Neurosurg, Med Sch, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Cell & Dev Biol, Med Sch, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Grad Program Immunol, Med Sch, Ann Arbor, MI 48109 USA

[4] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA

[5] Univ Michigan, Dept Internal Med, Med Sch, Ann Arbor, MI 48109 USA

[6] Univ Michigan, Dept Computat Med & Bioinformat, Med Sch, Ann Arbor, MI 48109 USA

[7] Univ Michigan, Dept Pathol, Med Sch, Ann Arbor, MI 48109 USA

[8] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Dept Oncol Sci, New York, NY 10029 USA

[9] Icahn Sch Med Mt Sinai, Dept Neurosurg, New York, NY 10029 USA

[10] Univ Michigan, Rogel Canc Ctr, Ann Arbor, MI 48109 USA

[11] Leloir Inst Fdn, Buenos Aires, DF, Argentina

[12] New York Univ, Dept Neurosurg, New York, NY 10018 USA

[13] Diamond Age Data Sci, 26 Ivaloo St, Somerville, MA 02143 USA

来源：

SCIENCE ADVANCES | 2021年 / 7卷 / 40期

基金：

美国国家卫生研究院;

关键词：

INTEGRATED GENOMIC ANALYSIS; IMMUNE; HETEROGENEITY; MUTATIONS; SUBTYPES; MICROENVIRONMENT; DIFFERENTIATION; ACTIVATION; PHENOTYPE; HIERARCHY;

D O I：

10.1126/sciadv.abh3243

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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/FIt3L) 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 pre-neutrophils. 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.

引用

页数：20

共 59 条

[1] Combined immunostimulation and conditional cytotoxic gene therapy provide long-term survival in a large glioma model [J].