Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo

Clin Exp Immunol. 2013 Jun;172(3):500-6. doi: 10.1111/cei.12069.


Recent basic and clinical studies have shown that the programmed death ligand (PD-L)/PD-1 pathway has a significant role in tumour immunity, and its blockade has a therapeutic potential against several human cancers. We hypothesized that anti-angiogeneic treatment might augment the efficacy of PD-1 blockade. To this end, we evaluated combining the blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2) in a murine cancer model using Colon-26 adenocarcinoma. Interestingly, simultaneous treatment with anti-PD-1 and anti-VEGFR2 monoclonal antibodies (mAbs) inhibited tumour growth synergistically in vivo without overt toxicity. Blocking VEGFR2 inhibited tumour neovascularization significantly, as demonstrated by the reduced number of microvessels, while PD-1 blockade had no impact on tumour angiogenesis. PD-1 blockade might promote T cell infiltration into tumours and significantly enhanced local immune activation, as shown by the up-regulation of several proinflammatory cytokine expressions. Importantly, VEGFR2 blockade did not interfere with T cell infiltration and immunological activation induced by PD-1 blockade. In conclusion, simultaneous blockade of PD-1 and VEGFR2 induced a synergistic in-vivo anti-tumour effect, possibly through different mechanisms that might not be mutually exclusive. This unique therapeutic strategy may hold significant promise for future clinical application.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / blood supply
  • Adenocarcinoma / immunology
  • Adenocarcinoma / therapy
  • Angiogenesis Inhibitors / administration & dosage
  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Cell Line, Tumor
  • Colonic Neoplasms / blood supply
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / therapy
  • Drug Synergism
  • Female
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms, Experimental / blood supply
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / therapy*
  • Neovascularization, Pathologic / prevention & control
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / immunology


  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Vascular Endothelial Growth Factor Receptor-2