Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival
Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival
复制标题
DOI：
10.1073/pnas.1525360113
复制
发表时间：
2016-04-19
影响因子：
11.1
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
--
作者：
Kloepper, Jonas;Riedemann, Lars;Jain, Rakesh K.
抑制血管内皮生长因子（VEGF）通路未能改善胶质母细胞瘤（GBM）患者的总体生存率。我们先前在临床前GBM模型中发现血管生成素-2（Ang-2）过表达损害了抗VEGF治疗的获益。在这里，我们研究了双重Ang-2/VEGF抑制是否可以克服抗VEGF治疗的抗性。我们用抑制VEGF（B20）或Ang-2/VEGF（CrossMab，A2 V）的抗体处理携带原位同基因（G1261）GBM或人（MGG 8）GBM异种移植物的小鼠。我们在G1261和MGG 8肿瘤模型中检查了治疗对肿瘤血管系统、免疫细胞群、肿瘤生长和存活的影响。我们发现，在显示高度异常的肿瘤血管系统的G1261模型中，与B20相比，A2 V降低了血管密度，延迟了肿瘤生长，并延长了生存期。在显示低程度血管异常的MGG 8模型中，A2 V未诱导肿瘤血管系统的显著变化，但仍延长了存活期。在G1261和MGG 8模型中，A2 V将前肿瘤M2巨噬细胞重编程为抗肿瘤M1表型。我们的研究结果表明，A2 V可以通过重新编程肿瘤免疫微环境和延迟肿瘤生长来延长GBM小鼠的生存期。
Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.