Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 16, Pages 4476-4481Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1525360113
Keywords
anti-angiogenic therapy; tumor microenvironment; anti-tumor immunity; macrophage polarization; microglia reprogramming
Categories
Funding
- NIH [P50CA165962, P01CA080124, KCA125440, R01CA126642, R35CA197743, R01CA159258, R01CA096915, R01HL106584, S10-RR027070, T32-CA073479, K12CA090354]
- National Cancer Institute/Federal Share Proton Beam Program Income
- Department of Defense Breast Cancer Research Innovator Award [W81XWH-10-1-0016]
- National Foundation for Cancer Research Fellow Award
- Hoffmann-La Roche
- German Research Foundation (DFG)
- Solidar-Immun Foundation
- Mildred Scheel Fellowship (Deutsche Krebshilfe)
- Aid for Cancer Research Foundation
- Susan G. Komen Postdoctoral Fellowship [PDF14301739]
- Affymetrix
- DFG
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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.
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