Advertisement

Cytotechnology

, Volume 38, Issue 1–3, pp 155–164 | Cite as

Induction of a T helper cell response against the tumor-associated antigen HER2 using monocyte-derived dendritic cells

  • J. Metzger
  • N. Nicklisch
  • P. Kufer
  • C. Peschel
  • P.B. Luppa
  • H. Bernhard
Article
  • 36 Downloads

Abstract

Tumor-reactive CD4+ T helper (Th) cells play a criticalrole in antitumor immunity, due to their ability to induceCD8+ T cell-mediated cytotoxic activity and humoralresponse. This study focuses on the in vitro generationand expansion of Th cells specific for the tumor-associatedantigen `human epidermal growth factor receptor-2' (HER2). Aprotocol for efficient HER2 presentation was developed usingautologous monocyte-derived dendritic cells (DC) as antigenpresenting cells (APC) and purified HER2 protein as antigensource. Our data suggest that DC pulsed with recombinantprotein of the extracellular domain (ECD) of HER2 (ECD/HER2)induce an ECD/HER2-specific Th cell response. This finding mayfacilitate the development of immunotherapy regimens withoutrequiring defined immunogenic epitopes of the antigen.

adoptive T cell transfer breast cancer dendritic cells HER2 Th cells tumor-associated antigen 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Albert ML, Pearce SF, Francisco LM, Sauter B, Roy P, Silverstein R& Bhardwaj N (1998) Immature dendritic cells phagocytose apoptotic cells via α v γ 5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J Exp Med 188: 1359–1368.Google Scholar
  2. Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, McMichael AJ& Davis MM (1996) Phenotypic analysis of antigen-specific T lymphocytes. Science 274: 94–96.Google Scholar
  3. Banchereau J& Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392: 245–252.Google Scholar
  4. Brossart P, Wirths S, Stuhler G, Reichardt VL, Kanz L& Brugger W (2000) Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. Blood 96: 3102–3108.Google Scholar
  5. Butcher EC& Picker LJ (1996) Lymphocyte homing and homeostasis. Science 272: 60–66.Google Scholar
  6. Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U, Levinson A& Ullrich A (1985) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230: 1132–1139.Google Scholar
  7. De Veerman M, Heirman C, Van Meirvenne S, Devos S, Corthals J, Moser M& Thielemans K (1999) Retrovirally transduced bone marrow-derived dendritic cells require CD4+ T cell help to elicit protective and therapeutic antitumor immunity. J Immunol 162: 144–151.Google Scholar
  8. Disis ML, Calenoff E, McLaughlin G, Murphy AE, Chen W, Groner B, Jeschke M, Lydon N, McGlynn E, Livingston RB, Moe R& Cheever MA (1994a) Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer. Cancer Res 54: 16–20.Google Scholar
  9. Disis ML, Smith JW, Murphy AE, Chen W& Cheever MA (1994b) In vitro generation of human cytolytic T-cells specific for peptides derived from the HER-2/neu protooncogene protein. Cancer Res 54: 1071–1076.Google Scholar
  10. Fisk B, Chesack B, Pollack MS, Wharton JT& Ioannides CG (1994) Oligopeptide induction of a cytotoxic T lymphocyte response to HER-2/neu proto-oncogene in vitro. Cell Immunol 157: 415–427.Google Scholar
  11. Greenberg PD (1986) Therapy of murine leukemia with cyclophosphamide and immune Lyt-2+ cells: cytolytic T cells can mediate eradication of disseminated leukemia. J Immunol 136: 1917–1922.Google Scholar
  12. Hanson HL, Donermeyer DL, Ikeda H, White JM, Shankaran V, Old LJ, Shiku H, Schreiber RD& Allen PM (2000) Eradication of established tumors by CD8+ T cell adoptive immunotherapy. Immunity 13: 265–276.Google Scholar
  13. Herr W, Schneider J, Lohse AW, Meyer zum Büschenfelde KH& Wölfel T (1996) Detection and quantification of blood-derived CD8+ T lymphocytes secreting tumor necrosis factor α in response to HLA-A2.1-binding melanoma and viral peptide antigens. J Immunol Methods 191: 131–142.Google Scholar
  14. Hynes NE& Stern DF (1994) The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta 1198: 165–184.Google Scholar
  15. Jäger E, Bernhard H, Romero P, Ringhoffer M, Arand M, Karbach J, Ilsemann C, Hagedorn M& Knuth A (1996) Generation of cytotoxic T-cell responses with synthetic melanoma-associated peptides in vivo: implications for tumor vaccines with melanoma-associated antigens. Int J Cancer 66: 162–169.Google Scholar
  16. Jonuleit H, Kühn U, Müller G, Steinbrink K, Paragnik L, Schmitt E, Knop J& Enk AH (1997) Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. Eur J Immunol 27: 3135–3142.Google Scholar
  17. Lenschow DJ, Walunas TL& Bluestone JA (1996) CD28/B7 system of T cell costimulation. Annu Rev Immunol 14: 233–258.Google Scholar
  18. Linehan DC, Goedegebuure PS, Peoples GE, Rogers SO& Eberlein TJ (1995) Tumor-specific and HLA-A2-restricted cytolysis by tumor-associated lymphocytes in human metastatic breast cancer. J Immunol 155: 4486–4491.Google Scholar
  19. Nouri-Shirazi M, Banchereau J, Bell D, Burkeholder S, Kraus ET, Davoust J& Palucka KA (2000) Dendritic cells capture killed tumor cells and present their antigens to elicit tumor-specific immune responses. J Immunol 165: 3797–3803.Google Scholar
  20. Ossendorp F, Mengedé E, Camps M, Filius R& Melief CJ (1998) Specific T helper cell requirement for optimal induction of cytotoxic T lymphocytes against major histocompatibility complex class II negative tumors. J Exp Med 187: 693–702.Google Scholar
  21. Peoples GE, Goedegebuure PS, Smith R, Linehan DC, Yoshino I& Eberlein TJ (1995) Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide. Proc Natl Acad Sci USA 92: 432–436.Google Scholar
  22. Sallusto F, Cella M, Danieli C& Lanzavecchia A (1995) Dendritic cells use macropinocytosis and the mannose receptor to concentrate antigen to the MHC class II compartment. Downregulation by cytokines and bacterial products. J Exp Med 182: 389–400.Google Scholar
  23. Shu SY& Rosenberg SA (1985) Adoptive immunotherapy of newly induced murine sarcomas. Cancer Res 45: 1657–1662.Google Scholar
  24. Slamon DJ& Clark GM (1988) Amplification of c-erbB-2 and aggressive human breast tumors? Science 240: 1795–1798.Google Scholar
  25. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A& Press MF (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244: 707–712.Google Scholar
  26. Thurner B, Haendle I, Röder C, Dieckmann D, Keikavoussi P, Jonuleit H, Bender A, Maczek C, Schreiner D, von den Driesch P, Brocker EB, Steinman RM, Enk A, Kampgen E& Schuler G (1999) Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 190: 1669–1678.Google Scholar
  27. Yee C, Savage PA, Lee PP, Davis MM& Greenberg PD (1999) Isolation of high avidity melanoma-reactive CTL from heterogeneous populations using peptide-MHC tetramers. J Immunol 162: 2227–2234.Google Scholar
  28. Zhou LJ& Tedder TF (1995) Human blood dendritic cells selectively express CD83, a member of the immunoglobulin superfamily. J Immunol 154: 3821–3835.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • J. Metzger
    • 1
  • N. Nicklisch
    • 1
  • P. Kufer
    • 2
  • C. Peschel
    • 1
  • P.B. Luppa
    • 3
  • H. Bernhard
    • 1
  1. 1.Institute for Hematology and OncologyKlinikum rechts der Isar der Technischen Universität MünchenMunichGermany
  2. 2.Institute for ImmunologyLudwig Maximilians-UniversitätMunichGermany
  3. 3.Institute for Clinical Chemistry and PathobiochemistryKlinikum rechts der Isar der Technischen Universität MünchenMunichGermany

Personalised recommendations