The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy.
Immature and unstable tumor vasculature provides an aberrant tumor microenvironment and leads to resistance of tumors to conventional therapy. Hence, normalization of tumor vessels has been reported to improve the effect of immuno-, chemo- and radiation therapy. However, the humoral factors, which can effectively induce maturation of tumor vasculature, have not been elucidated. In this study, we found that the novel peptide apelin and its receptor APJ can induce the morphological and functional maturation of blood vessels in tumors. This apelin-induced tumor vascular maturation enhances the efficacy of cancer dendritic cell-based immunotherapy and significantly suppresses tumor growth by promoting the infiltration of invariant natural killer T cells into the central region of the tumor and thereby robustly inducing apoptosis of tumor cells. Additionally, we showed APJ expression to be enhanced in the tumor endothelium in comparison with normal-state endothelial cells. These findings provide a new target for tumor vascular-specific maturation, which is expected to improve the efficacy of conventional cancer therapies.
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
H
H
Kidoya
N
N
Kunii
H
H
Naito
F
F
Muramatsu
Y
Y
Okamoto
T
T
Nakayama
N
N
Takakura
D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation / Q000187:drug effects; D017690:Cell Transplantation; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000637:transplantation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005699:Galactosylceramides / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology; D009369:Neoplasms / Q000098:blood supply* / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
C115436:APLN protein, human; C104575:APLNR protein, human; D000073861:Apelin; D000075244:Apelin Receptors; D005699:Galactosylceramides; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled