Induction of protective and therapeutic antitumor immunity by a DNA vaccine with C3d as a molecular adjuvant.
Although the critical role of complement component C3d as a molecular adjuvant in preventing virus infection is well established, its role in cancer therapies is unclear. In this study, we have engineered a DNA vaccine that expresses extracellular region of murine VEGFR-2 (FLK1(265-2493)) and 3 copies of C3d (C3d3), a component of complement as a molecular adjuvant, designed to increase antitumor immunity. VEGFR-2 has a more restricted expression on endothelial cells and is upregulated once these cells proliferate during angiogenesis in the tumor vasculature. Immunization of mice with vector encoding FLK1(265-2493) alone generated only background levels of anti-VEGFR-2 antibodies and slight inhibitory effect on tumor growth. However, the addition of C3d3 to the vaccine construct significantly augmented the anti-VEGFR-2 humoral immune response and inhibited the tumor growth. The antitumor activity induced by vaccination with vector encoding FLK1(265-2493)-C3d3 fusion protein was also demonstrated via growth inhibition of established tumors following passive transfer of immune serum from vaccinated mice. Our results suggest that vaccination with vector encoding FLK1(265-2493) with C3d3 as a molecular adjuvant induces adaptive humoral activity, which is directed against the murine VEGFR-2 and can significantly inhibit tumor growth, and that administration of C3d as a molecular adjuvant to increase antibodies levels to VEGFR-2 may provide an alternative treatment modality for cancer therapies.
Xu
Gui-lian
GL
Institute of Immunology PLA, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, People's Republic of China.
Zhang
Ke-qin
KQ
Guo
Bo
B
Zhao
Ting-ting
TT
Yang
Fei
F
Jiang
Man
M
Wang
Qing-hong
QH
Shang
Yu-hang
YH
Wu
Yu-zhang
YZ
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D015933:Complement C3d / Q000008:administration & dosage* / Q000276:immunology; D042783:Endothelial Cells / Q000276:immunology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D056724:Immunity, Humoral; D016219:Immunotherapy, Adoptive; D008297:Male; D008546:Melanoma, Experimental / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000008:administration & dosage / Q000276:immunology
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D015933:Complement C3d; D040301:Vascular Endothelial Growth Factor Receptor-2