A dual-function DNA vaccine encoding carcinoembryonic antigen and CD40 ligand trimer induces T cell-mediated protective immunity against colon cancer in carcinoembryonic antigen-transgenic mice.
A carcinoembryonic Ag (CEA)-based DNA vaccine encoding both CEA and CD40 ligand trimer achieved effective tumor-protective immunity against murine colon carcinoma in CEA-transgenic mice by activating both naive T cells and dendritic cells. Peripheral T cell tolerance to CEA was broken in a prophylactic model by this novel, dual-function DNA vaccine, whose efficacy was further enhanced by boosts with a recombinant Ab-IL-2 fusion protein (huKS1/4-IL-2). These conclusions are supported by four lines of evidence. First, a lethal challenge of MC38-CEA-KS Ag murine colon carcinoma cells was for the first time completely rejected in 100% of experimental animals treated by oral gavage of this DNA vaccine carried by attenuated Salmonella typhimurium, followed by five boosts with huKS1/4-IL-2. Second, specific activation of dendritic cells was indicated by their marked up-regulation in expression of costimulatory molecules B7.1 (CD80), B7.2 (CD86), and ICAM-1. Third, a decisive increase over control values was observed in both MHC class I Ag-restricted cytotoxicity of CTLs from successfully vaccinated mice and secretion of proinflammatory cytokines IFN-gamma and IL-12. Fourth, activation of CTLs was augmented, as indicated by up-regulation of activity markers LFA-1, CD25, CD28, and CD69. Taken together, these results suggest that a dual-function DNA vaccine encoding CEA and CD40 ligand trimer combined with tumor-targeted IL-2 may be a promising strategy for the rational development of DNA-based cancer vaccines for future clinical applications.
Xiang
R
R
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Primus
F J
FJ
Ruehlmann
J M
JM
Niethammer
A G
AG
Silletti
S
S
Lode
H N
HN
Dolman
C S
CS
Gillies
S D
SD
Reisfeld
R A
RA
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D002277:Carcinoma / Q000517:prevention & control*; D015815:Cell Adhesion Molecules; D003110:Colonic Neoplasms / Q000517:prevention & control*; D000071858:Epithelial Cell Adhesion Molecule; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014611:Vaccination; D019444:Vaccines, DNA / Q000627:therapeutic use*
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; C497965:Cd86 protein, mouse; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D023201:CD40 Ligand