Development of lung cancer treatment strategy using dendritic cells expressing anti-angiogenic function

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 16590752
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: KYUSHU UNIVERCITY
• Principal Investigator: NAKANISHI Yoichi Kyushu University, Graduate School of Medical Sciences, Professor, 大学院医学研究院, 教授 (20172356)
• Co-Investigator(Kenkyū-buntansha): TAKAYAMA Koichi Kyushu University, University Hospital, Assistant Professor, 大学病院, 講師 (50274444) ; HARADA Taishi Kyushu University, Graduate School of Medical Sciences, Research Associate, 大学院医学研究院, 助手 (10380619)
• Project Period (FY): 2004 – 2005
• Keywords: dendritic cell / anti tumor immune / vascular endothelial growth factor / galactosylceramide

Research Abstract

Vascular endothelial growth factor has an action that obstructs the maturity of the dendritic cell in blood. Then, soluble VEGF receptor gene was introduced into the dendritic cell first in this research, and making the dendritic cell that rivaled the tumor producing VEGF was tried. Adenovirus vector was used for this gene transduction. The dendritic cells were differentiated from the mouse marrow cells by addition of GM-CSF and IL-4 in the culture media. Soluble VEGF receptor cDNA was consisted in the extracellular domain of wild type VEGF receptor and human IgG Fc portion. The gene introduction efficiency to the dendritic cell correlated to the density of the infection virus, and considerable amount of soluble VEGF receptor was confirmed in the culture media with infected cells at moi 50. The culture supernatant of the infected cell obstructed DNA synthesis of vasucular endothelial cell by human VEGF. DC cells maturation is inhibited in the presence of VEGF, and the expression of the B7 molecule and the MHC molecule was suppressed both, and the proliferation potency of T cell has also decreased. On the other hand, the dendritic cell that introduced soluble VEGF receptor gene promoted the expression of B7 and the MHC molecule, and also maintained the proliferation potency of T cell against VEGF addition into medium. Next, alpha-galactosylceramide (a-GalCer) was used as a method of improving the antitumor activity of the dendritic cell. α-GalCer is presented in the NKT cell through MHC class I molecule, CD1d that express on the dendritic cell. Then, a-GalCer was administered to an immature or mature dendritic cell, and the expression of MHC class I, II, and CD86, and anti-tumor effect was examined. Dendritic cell pulsed with α-GalCer showed the significant suppression of tumor growth and improved the survival time.