title: Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy.
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.
authors.affiliation: 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, USA.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Huang
authors.forename: Jianping
authors.initials: J
authors.lastname: Yuan
authors.forename: Elda
authors.initials: E
authors.lastname: Righi
authors.forename: Walid S
authors.initials: WS
authors.lastname: Kamoun
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.forename: Jean
authors.initials: J
authors.lastname: Nezivar
authors.forename: Michael
authors.initials: M
authors.lastname: Santosuosso
authors.forename: John D
authors.initials: JD
authors.lastname: Martin
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Martin
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vianello
authors.forename: Pierre
authors.initials: P
authors.lastname: Leblanc
authors.forename: Lance L
authors.initials: LL
authors.lastname: Munn
authors.forename: Peigen
authors.initials: P
authors.lastname: Huang
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.forename: Mark C
authors.initials: MC
authors.lastname: Poznansky
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000276:immunology; D005260:Female; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D059016:Tumor Microenvironment; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology
chemical_list: D020533:Angiogenesis Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2