title: Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo.
abstract: 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.
authors.affiliation: Department of Surgery, Nara Medical University, Nara, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yasuda
authors.forename: M
authors.initials: M
authors.lastname: Sho
authors.forename: I
authors.initials: I
authors.lastname: Yamato
authors.forename: H
authors.initials: H
authors.lastname: Yoshiji
authors.forename: K
authors.initials: K
authors.lastname: Wakatsuki
authors.forename: S
authors.initials: S
authors.lastname: Nishiwada
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: Y
authors.initials: Y
authors.lastname: Nakajima
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000276:immunology / Q000628:therapy; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000098:blood supply / Q000276:immunology / Q000628:therapy; D004357:Drug Synergism; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D040301:Vascular Endothelial Growth Factor Receptor-2