Antibody and CD8+ T cell responses against HER2/neu required for tumor eradication after DNA immunization with a Flt-3 ligand fusion vaccine Journal Article
| Authors: | Orlandi, F.; Venanzi, F. M.; Concetti, A.; Yamauchi, H.; Tiwari, S.; Norton, L.; Wolchok, J. D.; Houghton, A. N.; Gregor, P. D. |
| Article Title: | Antibody and CD8+ T cell responses against HER2/neu required for tumor eradication after DNA immunization with a Flt-3 ligand fusion vaccine |
| Abstract: | Purpose: 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. Experimental Design: 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 neuprotein 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. ©2007 American Association for Cancer Research. |
| Keywords: | adolescent; controlled study; nonhuman; protein localization; cd8+ t lymphocyte; cd8-positive t-lymphocytes; t-lymphocytes; animal cell; mouse; animals; mice; breast cancer; benzyloxycarbonylleucylleucylleucinal; epidermal growth factor receptor 2; animal experiment; animal model; membrane proteins; cell line, tumor; cercopithecus aethiops; cos cells; time factors; endoplasmic reticulum; antigen presentation; dna; cellular immunity; cancer vaccines; immunogenicity; antibody response; ligands; adoptive transfer; tumor immunity; microscopy, fluorescence; dna vaccine; protein structure, tertiary; neoplasm transplantation; flt3 ligand; tumor rejection; humoral immunity; neuraminidase; vaccines, dna; dna immunization; complementary dna |
| Journal Title: | Clinical Cancer Research |
| Volume: | 13 |
| Issue: | 20 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2007-10-15 |
| Start Page: | 6195 |
| End Page: | 6203 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-07-0258 |
| PUBMED: | 17947487 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 15" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus" |
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