title: Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy.
abstract: OBJECTIVE
  The purpose of the present study was to evaluate granulocyte macrophage colony-stimulating factor (GM-CSF)-secreting tumor cell immunotherapy in combination with vascular endothelial growth factor (VEGF) blockage in preclinical models.
  
  
  METHODS
  Survival and immune response were monitored in the B16 melanoma and the CT26 colon carcinoma models. VEGF blockade was achieved by using a recombinant adeno-associated virus vector expressing a soluble VEGF receptor consisting of selected domains of the VEGF receptors 1 and 2 (termed sVEGFR1/R2). Dendritic cell and tumor infiltrating lymphocyte activation status and numbers were evaluated by fluorescence-activated cell sorting analysis. Regulatory T cells were quantified by their CD4+CD25hi and CD4+FoxP3+ phenotype.
  
  
  RESULTS
  The present study established that GM-CSF-secreting tumor cell immunotherapy with VEGF blockade significantly prolonged the survival of tumor-bearing mice. Enhanced anti-tumor protection correlated with an increased number of activated CD4+ and CD8+ tumor-infiltrating T cells and a pronounced decrease in the number of suppressive regulatory T cells residing in the tumor. Conversely, overexpression of VEGF from tumors resulted in elevated numbers of regulatory T cells in the tumor, suggesting a novel mechanism of VEGF-mediated immune suppression at the tumor site.
  
  
  CONCLUSIONS
  GM-CSF-secreting cancer immunotherapy and VEGF blockade increases the i.t. ratio of effector to regulatory T cells to provide enhanced antitumor responses. This therapeutic combination may prove to be an effective strategy for the treatment of patients with cancer.
authors.affiliation: Cell Genesys, Inc., South San Francisco, California 94080, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Li
authors.forename: Alshad S
authors.initials: AS
authors.lastname: Lalani
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Harding
authors.forename: Bo
authors.initials: B
authors.lastname: Luan
authors.forename: Kathryn
authors.initials: K
authors.lastname: Koprivnikar
authors.forename: Guang
authors.initials: G
authors.lastname: Huan Tu
authors.forename: Rodney
authors.initials: R
authors.lastname: Prell
authors.forename: Melinda J
authors.initials: MJ
authors.lastname: VanRoey
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Simmons
authors.forename: Karin
authors.initials: K
authors.lastname: Jooss
mesh_terms: D000818:Animals; D017209:Apoptosis; D002277:Carcinoma / Q000628:therapy; D002452:Cell Count; D003110:Colonic Neoplasms / Q000628:therapy; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000166:cytology; D053222:Fas Ligand Protein / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology; D008546:Melanoma, Experimental / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000401:mortality / Q000628:therapy*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019014:fas Receptor / Q000032:analysis
chemical_list: D053222:Fas Ligand Protein; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D019014:fas Receptor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D040262:Receptors, Vascular Endothelial Growth Factor