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: Masahiko Sugiyama, Yoshihiro Kakeji, Shunichi Tsujitani, Yui Harada, Mitsuho Onimaru, Kumi Yoshida, Sakura Tanaka, Yasunori Emi, Masaru Morita, Yosuke Morodomi, Mamoru Hasegawa, Yoshihiko Maehara, Yoshikazu Yonemitsu
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 3 Pg. 540-9 (Mar 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21209070 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Antineoplastic Agents
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Animals
• Antineoplastic Agents (immunology)
• Ascites (etiology, immunology, therapy)
• Colonic Neoplasms (complications, immunology, therapy)
• Dendritic Cells (immunology, metabolism)
• Flow Cytometry
• Gene Expression
• Gene Transfer Techniques
• Genetic Engineering
• Humans
• Immunotherapy (methods)
• Mice
• Mice, Inbred BALB C
• Reverse Transcriptase Polymerase Chain Reaction
• Sendai virus (genetics)
• Survival
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)
• Vascular Endothelial Growth Factor Receptor-1 (genetics)