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Cancer Immunology, Immunotherapy

, Volume 58, Issue 5, pp 653–664 | Cite as

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

  • Simona VertuaniEmail author
  • Chiara Triulzi
  • Anna Karin Roos
  • Jehad Charo
  • Håkan Norell
  • François Lemonnier
  • Pavel Pisa
  • Barbara Seliger
  • Rolf Kiessling
Original Article

Abstract

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.

Keywords

DNA vaccine HER-2 MHC class I Antigen processing 

Abbreviations

APM

Antigen processing machinery

HER-2

ErbB-2

HHD

HLA-A2-Db

ICCS

Intra-cellular cytokine staining

MC

Methylcholanthrene

Notes

Acknowledgments

This work was supported by grants to R. K from the Swedish Cancer Society, the Cancer Society of Stockholm, the European Union (Grants "ENACT" and "DC-THERA"), the Karolinska Institutet, and "ALF-Project" grants from the Stockholm City Council.

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Simona Vertuani
    • 1
    • 6
    Email author
  • Chiara Triulzi
    • 1
  • Anna Karin Roos
    • 1
  • Jehad Charo
    • 2
  • Håkan Norell
    • 3
  • François Lemonnier
    • 4
  • Pavel Pisa
    • 1
  • Barbara Seliger
    • 5
  • Rolf Kiessling
    • 1
  1. 1.Department of Oncology-PathologyKarolinska InstitutetStockholmSweden
  2. 2.Max-Delbrück-CentrumBerlinGermany
  3. 3.Hollings Cancer CenterMedical University of South CarolinaCharlestonUSA
  4. 4.Unité d’Immunité Cellulaire AntiviraleInstitut PasteurParisFrance
  5. 5.Institute of Medical ImmunologyMartin Luther University Halle-WittenbergHalleGermany
  6. 6.Immune and Gene Therapy Unit, Cancer Centrum KarolinskaKarolinska HospitalStockholmSweden

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