HER-2/neu mediated down-regulation of MHC class I antigen processing prevents CTL-mediated tumor recognition upon DNA vaccination in HLA-A2 transgenic mice.
To study DNA vaccination directed against human HER-2 in the HHD mouse Tg strain, we created a novel HER-2-expressing syngeneic tumor transplantation model. We found that a DNA vaccine encoding the full length HER-2 DNA protected HHD mice from HER-2(+) tumor challenge by a CTL independent mechanism. A more efficient approach to induce HLA-A2 restricted CTLs, through immunization with a multi-epitope DNA vaccine expressing the HLA-A2 restricted HER-2 369-377, 435-443 and 689-697 epitopes, resulted in high numbers of peptide specific T cells but failed to induce tumor protection. Subsequently we discovered that HER-2 transfected tumor cells down-regulated MHC class I antigen expression and exhibited a series of defects in the antigen processing pathway which impaired the capacity to produce and display MHC class I peptide-ligands to specific CTLs. Our data demonstrate that HER-2 transfection is associated with defects in the MHC class I presentation pathway, which may be the underlying mechanism behind the inability of CTLs to recognize tumors in this HLA-A2 transgenic model. As defective MHC class I presentation may be a common characteristic of HER-2 expressing tumors, vaccines targeting HER-2 should aim at inducing an integrated immune response where also CD4(+) T cells and antibodies are important components.
Vertuani
Simona
S
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. Simona.Vertuani@ki.se
Triulzi
Chiara
C
Roos
Anna Karin
AK
Charo
Jehad
J
Norell
Håkan
H
Lemonnier
François
F
Pisa
Pavel
P
Seliger
Barbara
B
Kiessling
Rolf
R
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001483:Base Sequence; D019496:Cancer Vaccines / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005805:Genes, MHC Class I; D018734:Genes, erbB-2; D015789:HLA-A2 Antigen / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008212:Lymphocyte Depletion; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D019444:Vaccines, DNA / Q000276:immunology*
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D019444:Vaccines, DNA; C508053:ERBB2 protein, human