Tumor Vessel Normalization, Immunostimulatory Reprogramming, and Improved Survival in Glioblastoma with Combined Inhibition of PD-1, Angiopoietin-2, and VEGF

Cancer Immunol Res. 2019 Dec;7(12):1910-1927. doi: 10.1158/2326-6066.CIR-18-0865. Epub 2019 Oct 9.


Glioblastoma (GBM) is a non-T-cell-inflamed cancer characterized by an immunosuppressive microenvironment that impedes dendritic cell maturation and T-cell cytotoxicity. Proangiogenic cytokines such as VEGF and angiopoietin-2 (Ang-2) have high expression in glioblastoma in a cell-specific manner and not only drive tumor angiogenesis and vascular permeability but also negatively regulate T-lymphocyte and innate immune cell responses. Consequently, the alleviation of immunosuppression might be a prerequisite for successful immune checkpoint therapy in GBM. We here combined antiangiogenic and immune checkpoint therapy and demonstrated improved therapeutic efficacy in syngeneic, orthotopic GBM models. We observed that blockade of VEGF, Ang-2, and programmed cell death protein-1 (PD-1) significantly extended survival compared with vascular targeting alone. In the GBM microenvironment, triple therapy increased the numbers of CTLs, which inversely correlated with myeloid-derived suppressor cells and regulatory T cells. Transcriptome analysis of GBM microvessels indicated a global vascular normalization that was highest after triple therapy. Our results propose a rationale to overcome tumor immunosuppression and the current limitations of VEGF monotherapy by integrating the synergistic effects of VEGF/Ang-2 and PD-1 blockade to reinforce antitumor immunity through a normalized vasculature.

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Angiopoietin-2 / antagonists & inhibitors*
  • Animals
  • Antineoplastic Agents, Immunological / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bevacizumab / therapeutic use
  • Brain / blood supply
  • Brain Neoplasms / blood supply
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / immunology
  • Brain Neoplasms / mortality
  • Cell Line, Tumor
  • Female
  • Glioblastoma / blood supply
  • Glioblastoma / drug therapy*
  • Glioblastoma / immunology
  • Glioblastoma / mortality
  • Humans
  • Immune Tolerance / drug effects
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*


  • Angiogenesis Inhibitors
  • Angiopoietin-2
  • Angpt2 protein, mouse
  • Antineoplastic Agents, Immunological
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Bevacizumab