title: Antagonism of VEGF by genetically engineered dendritic cells is essential to induce antitumor immunity against malignant ascites.
abstract: Malignant ascitis (MA) is a highly intractable and immunotherapy-resistant state of advanced gastrointestinal and ovarian cancers. Using a murine model of MA with CT26 colon cancer cells, we here determined that the imbalance between the VEGF-A/vascular permeability factor and its decoy receptor, soluble fms-like tryrosine kinase receptor-1 (sFLT-1), was a major cause of MA resistance to dendritic cell (DC)-based immunotherapy. We found that the ratio of VEGF-A/sFLT-1 was increased not only in murine but also in human MA, and F-gene-deleted recombinant Sendai virus (rSeV/dF)-mediated secretion of human sFLT-1 by DCs augmented not only the activity of DCs themselves, but also dramatically improved the survival of tumor-bearing animals associated with enhanced CTL activity and its infiltration to peritoneal tumors. These findings were not seen in immunodeficient mice, indicating that a VEGF-A/sFLT-1 imbalance is critical for determining the antitumor immune response by DC-vaccination therapy against MA.
authors.affiliation: R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Rm 505 Collaborative Research Station II, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sugiyama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kakeji
authors.forename: Shunichi
authors.initials: S
authors.lastname: Tsujitani
authors.forename: Yui
authors.initials: Y
authors.lastname: Harada
authors.forename: Mitsuho
authors.initials: M
authors.lastname: Onimaru
authors.forename: Kumi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Sakura
authors.initials: S
authors.lastname: Tanaka
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Emi
authors.forename: Masaru
authors.initials: M
authors.lastname: Morita
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Morodomi
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Yonemitsu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology; D001201:Ascites / Q000209:etiology / Q000276:immunology* / Q000628:therapy; D003110:Colonic Neoplasms / Q000150:complications / Q000276:immunology* / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D005434:Flow Cytometry; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005818:Genetic Engineering; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029082:Sendai virus / Q000235:genetics; D013534:Survival; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1