Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy

Edwin L. Steele Laboratory of Tumor Biology, Department of Radiation Oncology and Vaccine and Immunotherapy Center, Infectious Diseases Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 10/2012; 109(43):17561-17566. DOI: 10.1073/pnas.1215397109

ABSTRACT 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.


Available from: Fabrizio Vianello, Apr 27, 2015
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