Protective immunity against human carcinoembryonic antigen (CEA) induced by an oral DNA vaccine in CEA-transgenic mice.
Peripheral T-cell tolerance toward human carcinoembryonic self-antigen (CEA) was broken in CEA-transgenic C57BL/6J mice by an oral CEA-based DNA vaccine. This vaccine, delivered by the live, attenuated AroA- strain of Salmonella typhimurium (SL7207), induced tumor-protective immunity mediated by MHC class I-restricted CD8+ T cells. Activation of these T cells was indicated by increased secretion of proinflammatory cytokines IFN-gamma, interleukin (IL)-12 and granulocyte/macrophage-colony stimulating factor, as well as specific tumor rejection and growth suppression in vaccinated CEA-transgenic mice after a lethal challenge with murine MC38 colon carcinoma cells. These tumor cells were double transfected with CEA and the human epithelial cell adhesion molecule (Ep-CAM)/KSA and consequently served as a docking site for a recombinant antibody-IL2 fusion protein (KS1/4-IL2) recognizing KSA. Importantly, the efficacy of the tumor-protective immune response was markedly increased by boosts with this antibody-IL2 fusion protein, resulting in more effective tumor rejection coupled with increased expression of costimulatory molecules B7.2/B7.2 and intercellular adhesion molecule 1 (ICAM-1) on dendritic cells and intensified release of proinflammatory cytokines IFN-gamma, IL-12, and granulocyte/macrophage-colony stimulating factor from T cells of successfully vaccinated CEA-transgenic C57BL/6J mice. Increased T-cell activation mediated by boosts with KS1/4-IL2 fusion protein after tumor cell challenge was further indicated by expanded expression of T-cell activation markers CD25, CD28, CD69, and LFA-1. The application of such CEA-based DNA vaccines and its further improved versions may ultimately prove useful in combination therapies directed against human carcinomas expressing CEA self-antigens.
Xiang
R
R
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Silletti
S
S
Lode
H N
HN
Dolman
C S
CS
Ruehlmann
J M
JM
Niethammer
A G
AG
Pertl
U
U
Gillies
S D
SD
Primus
F J
FJ
Reisfeld
R A
RA
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D000071858:Epithelial Cell Adhesion Molecule; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010957:Plasmids / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D019444:Vaccines, DNA
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D015815:Cell Adhesion Molecules; D016207:Cytokines; D000071858:Epithelial Cell Adhesion Molecule; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor