TY - JOUR
T1 - Antagonism of VEGF by genetically engineered dendritic cells is essential to induce antitumor immunity against malignant ascites
AU - Sugiyama, Masahiko
AU - Kakeji, Yoshihiro
AU - Tsujitani, Shunichi
AU - Harada, Yui
AU - Onimaru, Mitsuho
AU - Yoshida, Kumi
AU - Tanaka, Sakura
AU - Emi, Yasunori
AU - Morita, Masaru
AU - Morodomi, Yosuke
AU - Hasegawa, Mamoru
AU - Maehara, Yoshihiko
AU - Yonemitsu, Yoshikazu
PY - 2011/3
Y1 - 2011/3
N2 - Malignant ascitis (MA) is a highly intractable and immunotherapy-resistant state of advanced gastro-intestinal 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.
AB - Malignant ascitis (MA) is a highly intractable and immunotherapy-resistant state of advanced gastro-intestinal 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.
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U2 - 10.1158/1535-7163.MCT-10-0479
DO - 10.1158/1535-7163.MCT-10-0479
M3 - Article
C2 - 21209070
AN - SCOPUS:79955765281
VL - 10
SP - 540
EP - 549
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 3
ER -