Antibody and CD8+ T cell responses against HER2/neu required for tumor eradication after DNA immunization with a Flt-3 ligand fusion vaccine.
OBJECTIVE
HER2/neu is frequently overexpressed in breast cancer. In a mouse model, vaccination with HER2/neu DNA elicits antibodies that confer partial protection against tumor challenge.


METHODS
To enhance antitumor immunity, we fused cDNA encoding Flt-3 ligand (FL) to the rat HER2/neu extracellular domain (neu), generating a chimeric FLneu molecule. FLneu and neu DNA vaccines were compared for immunogenicity and their ability to protect mice from tumor challenge.


RESULTS
The neu vaccine generated a HER2/neu-specific antibody response. In contrast, vaccination with FLneu induced CD8+ T cells specific for HER2/neu but a negligible anti-HER2/neu antibody response. The switch from an antibody-mediated to T cell-mediated response was due to different intracellular localization of neu and FLneu. Although the neu protein was secreted, the FLneu protein was retained inside the cell, co-localizing with the endoplasmic reticulum, facilitating processing and presentation to T cells. The neu and FLneu vaccines individually conferred only weak tumor immunity. However, efficient tumor rejection was seen when neu and FLneu were combined, inducing both strong anti-HER2/neu-specific antibody and T cell responses. Adoptive transfer of both immune CD8+ T cells and immune sera from immunized mice was required to confer tumor immunity in naïve hosts.


CONCLUSIONS
These results show that active induction of both humoral and cellular immunity to HER2/neu is required for efficient tumor protection, and that neither response alone is sufficient.
Orlandi
Francesca
F
Swim Across America Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Venanzi
Franco M
FM
Concetti
Antonio
A
Yamauchi
Hanako
H
Tiwari
Shakuntala
S
Norton
Larry
L
Wolchok
Jedd D
JD
Houghton
Alan N
AN
Gregor
Polly D
PD
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D019556:COS Cells; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004247:DNA / Q000737:chemistry*; D005260:Female; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry*; D051379:Mice; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009439:Neuraminidase / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D019444:Vaccines, DNA / Q000737:chemistry
D019496:Cancer Vaccines; D008024:Ligands; D008565:Membrane Proteins; D019444:Vaccines, DNA; C084881:flt3 ligand protein; D004247:DNA; C403285:NEU2 protein, human; D009439:Neuraminidase