Document Detail

Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy.
MedLine Citation:
PMID:  23045683     Owner:  NLM     Status:  MEDLINE    
The recent approval of a prostate cancer vaccine has renewed hope for anticancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they often are used at high doses in the clinic to prune tumor vessels and paradoxically may compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower vascular-normalizing doses, but not high antivascular/antiangiogenic doses, of an anti-VEGF receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses in polarizing tumor-associated macrophages from an immune inhibitory M2-like phenotype toward an immune stimulatory M1-like phenotype and in facilitating CD4(+) and CD8(+) T-cell tumor infiltration. Based on this mechanism, scheduling lower-dose anti-VEGFR2 therapy with T-cell activation induced by a whole cancer cell vaccine therapy enhanced anticancer efficacy in a CD8(+) T-cell-dependent manner in both immune-tolerant and immunogenic murine breast cancer models. These findings indicate that vascular-normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a strategy to use antiangiogenic agents in breast cancer more effectively with active immunotherapy and potentially other anticancer therapies.
Yuhui Huang; Jianping Yuan; Elda Righi; Walid S Kamoun; Marek Ancukiewicz; Jean Nezivar; Michael Santosuosso; John D Martin; Margaret R Martin; Fabrizio Vianello; Pierre Leblanc; Lance L Munn; Peigen Huang; Dan G Duda; Dai Fukumura; Rakesh K Jain; Mark C Poznansky
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-10-08
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-24     Completed Date:  2013-01-07     Revised Date:  2014-01-14    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  17561-6     Citation Subset:  IM    
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MeSH Terms
Angiogenesis Inhibitors / pharmacology*
Breast Neoplasms / blood supply*,  immunology
Tumor Microenvironment*
Vascular Endothelial Growth Factor Receptor-2 / immunology
Grant Support
R01 CA149285/CA/NCI NIH HHS; R01 HL106584/HL/NHLBI NIH HHS; R01-CA096915/CA/NCI NIH HHS; R01-CA115767/CA/NCI NIH HHS; R01-CA126642/CA/NCI NIH HHS; R01-CA159258/CA/NCI NIH HHS; R21-CA139168/CA/NCI NIH HHS
Reg. No./Substance:
0/Angiogenesis Inhibitors; EC Endothelial Growth Factor Receptor-2

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