Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy
- 8 October 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (43), 17561-17566
- https://doi.org/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.Keywords
This publication has 39 references indexed in Scilit:
- Tumor-targeted TNFα stabilizes tumor vessels and enhances active immunotherapyProceedings of the National Academy of Sciences of the United States of America, 2012
- Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent mannerNature Nanotechnology, 2012
- Therapeutic Cancer Vaccines: Current Status and Moving ForwardJNCI Journal of the National Cancer Institute, 2012
- Receptor Tyrosine Kinases and TLR/IL1Rs Unexpectedly Activate Myeloid Cell PI3Kγ, A Single Convergent Point Promoting Tumor Inflammation and ProgressionCancer Cell, 2011
- Consequence of dose scheduling of sunitinib on host immune response elements and vaccine combination therapyInternational Journal of Cancer, 2011
- Molecular mechanisms and clinical applications of angiogenesisNature, 2011
- Polarization of Tumor-Associated Macrophages: A Novel Strategy for Vascular Normalization and Antitumor ImmunityCancer Cell, 2011
- HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironmentThe Journal of Experimental Medicine, 2010
- Myeloid Cells in the Tumor Microenvironment: Modulation of Tumor Angiogenesis and Tumor InflammationJournal of Oncology, 2010
- Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast CancerThe New England Journal of Medicine, 2007