G-CSF secreted by mutant IDH1 glioma stem cells abolishes myeloid cell immunosuppression and enhances the efficacy of immunotherapy.
G-CSF secreted by mutant IDH1 glioma stem cells abolishes myeloid cell immunosuppression and enhances the efficacy of immunotherapy.
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DOI：
10.1126/sciadv.abh3243
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发表时间：
2021-10
期刊：
影响因子：
13.6
通讯作者：
Castro MG
中科院分区：
文献类型：
--
作者：
Alghamri MS;McClellan BL;Avvari RP;Thalla R;Carney S;Hartlage CS;Haase S;Ventosa M;Taher A;Kamran N;Zhang L;Faisal SM;Núñez FJ;Garcia-Fabiani MB;Al-Holou WN;Orringer D;Hervey-Jumper S;Heth J;Patil PG;Eddy K;Merajver SD;Ulintz PJ;Welch J;Gao C;Liu J;Núñez G;Hambardzumyan D;Lowenstein PR;Castro MG
突变IDH 1胶质瘤被非抑制性未成熟髓样细胞浸润，导致对免疫治疗的反应增强。突变型异柠檬酸脱氢酶1（mIDH 1）合成癌代谢物2-羟基戊二酸（2 HG），其通过抑制DNA和组蛋白去甲基化酶来促进胶质瘤细胞转录组的表观遗传重编程。我们表明，免疫刺激基因治疗（TK/Flt 3L）的疗效增强mIDH 1神经胶质瘤，由于骨髓细胞的隔间浸润肿瘤微环境（TME）的重编程。我们发现浸润mIDH 1 TME的未成熟髓样细胞主要是非抑制性中性粒细胞和前中性粒细胞。髓样细胞重编程由mIDH 1胶质瘤干/祖细胞样细胞分泌的粒细胞集落刺激因子（G-CSF）触发。在携带mIDH 1神经胶质瘤的小鼠中阻断G-CSF可恢复肿瘤浸润性骨髓细胞的抑制潜力，加速肿瘤进展。我们证明，G-CSF重新编程骨髓粒细胞生成，导致在mIDH 1胶质瘤TME内的非抑制性髓样细胞，并提高免疫刺激基因治疗的疗效。
Mutant IDH1 gliomas are infiltrated by nonsuppressive immature myeloid cells, resulting in enhanced response to immunotherapy. 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.
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影响因子：
10.5
作者：
Amankulor NM;Kim Y;Arora S;Kargl J;Szulzewsky F;Hanke M;Margineantu DH;Rao A;Bolouri H;Delrow J;Hockenbery D;Houghton AM;Holland EC
通讯作者：
Holland EC
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
DOI：
10.1126/science.1198704
发表时间：
2011-05-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bendall SC;Simonds EF;Qiu P;Amir el-AD;Krutzik PO;Finck R;Bruggner RV;Melamed R;Trejo A;Ornatsky OI;Balderas RS;Plevritis SK;Sachs K;Pe'er D;Tanner SD;Nolan GP
通讯作者：
Nolan GP
影响因子：
11.2
作者：
Chang AL;Miska J;Wainwright DA;Dey M;Rivetta CV;Yu D;Kanojia D;Pituch KC;Qiao J;Pytel P;Han Y;Wu M;Zhang L;Horbinski CM;Ahmed AU;Lesniak MS
通讯作者：
Lesniak MS
影响因子：
7.1
作者：
Cimino PJ;Zager M;McFerrin L;Wirsching HG;Bolouri H;Hentschel B;von Deimling A;Jones D;Reifenberger G;Weller M;Holland EC
通讯作者：
Holland EC