Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy.
Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy.
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DOI：
10.1016/j.celrep.2015.03.055
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发表时间：
2015-04-28
期刊：
影响因子：
8.8
通讯作者：
Bergers G
中科院分区：
文献类型：
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作者：
Rivera LB;Meyronet D;Hervieu V;Frederick MJ;Bergsland E;Bergers G
抗血管生成疗法在临床上是常用的，但其有益效果是短暂的，导致肿瘤在几个月内复发。在这里，我们证明了针对VEGF/VEGFR通路的血管生成抑制剂的功效依赖于胰腺神经内分泌和乳腺肿瘤小鼠模型中血管生成抑制和免疫估计趋化因子CXCL 14的诱导。作为响应，肿瘤通过激活所有CD 11b+细胞中的PI 3 K信号传导重新启动血管生成和免疫抑制，使肿瘤对VEGF/VEGFR抑制无反应。适应性抗性也与Gr 1 + CD 11b+细胞的增加相关，但靶向Gr 1+细胞不足以进一步敏化血管生成阻断，因为TAM将补偿其缺乏，反之亦然，导致不同免疫细胞群体的振荡模式。然而，CD 11b+骨髓细胞中的PI 3 K抑制产生了持久的血管生成抑制和免疫刺激环境，其中抗血管生成治疗仍然有效。
Antiangiogenic therapy is commonly used in the clinic but its beneficial effects are short-lived leading to tumor relapse within months. Here, we demonstrate that the efficacy of angiogenic inhibitors targeting the VEGF/VEGFR pathway is dependent on the induction of the angiostatic and immunestimulatory chemokine CXCL14 in mouse models of pancreatic neuroendocrine and mammary tumors. In response, tumors reinitiated angiogenesis and immune-suppression by activating PI3K-signaling in all CD11b+ cells rendering tumors non-responsive to VEGF/VEGFR inhibition. Adaptive resistance was also associated with an increase in Gr1+CD11b+ cells, but targeting Gr1+ cells was not sufficient to further sensitize angiogenic blockade as TAM would compensate for their lack and vice versa leading to an oscillating pattern of distinct immune cell populations. However, PI3K inhibition in CD11b+ myeloid cells generated an enduring angiostatic and immune-stimulatory environment in which anti-angiogenic therapy remained efficient.
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影响因子：
4.4
作者：
Bouzin, Caroline;Brouet, Agnes;Feron, Olivier
通讯作者：
Feron, Olivier
影响因子：
64.5
作者：
Fischer, Christian;Jonckx, Bart;Carmeliet, Peter
通讯作者：
Carmeliet, Peter
影响因子：
50.3
作者：
Casanovas, O;Hicklin, DJ;Hanahan, D
通讯作者：
Hanahan, D
影响因子：
64.8
作者：
HANAHAN, D
通讯作者：
HANAHAN, D
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
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作者：
通讯作者：
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