Skip to main content

Advertisement

SpringerLink
Log in

Spontaneous Proliferation and Type 2 Cytokine Secretion by CD4+T Cells in Patients with Metastatic Melanoma Vaccinated with Antigen-Pulsed Dendritic Cells

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

We observed the induction of spontaneous, i.e., without adding exogenous antigen, in vitro proliferation of PBMCs from patients with stage IV melanoma who underwent repeated vaccinations with antigen-loaded dendritic cells (DCs) derived from CD34+ hematopoietic progenitors (CD34-DCs). Proliferating cells are CD4+T cells. Their proliferation is dependent on (1) CD11c+ myeloid DCs, since their depletion from PBMCs abolishes it; and (2) IL-2, as it can be blocked by neutralizing anti-IL-2 antibodies. Spontaneous proliferation is associated to the secretion of type 2 cytokines. To analyze the frequency of spontaneous proliferation induction in the cohort of 18 vaccinated patients, an index of spontaneous proliferation was defined as a ratio of PBMCs proliferation from post- vs pre-DC vaccination blood samples. Ten out of sixteen analyzed patients showed an index > 2. The index of spontaneous proliferation correlates with antigen-specific PBMC proliferation to the vaccine antigen KLH. Furthermore, both spontaneous- and antigen-specific proliferation in PBMC cultures are dependent on blood myeloid DCs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Knuth A, Wolfel T, Klehmann E, Boon T, Meyer zum Buschenfelde KH: Cytolytic T-cell clones against an autologous human melanoma: Specificity study and definition of three antigens by immunoselection. Proc Natl Acad Sci USA 86:2804, 1989

    CAS  PubMed  Google Scholar 

  2. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A, Boon T: A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254:1643, 1991

    PubMed  Google Scholar 

  3. Rosenberg SA: Cancer vaccines based on the identification of genes encoding cancer regression antigens. Immunol Today 18:175, 1997

    Article  CAS  PubMed  Google Scholar 

  4. Caux C, Dezutter-Dambuyant C, Schmitt D, Banchereau J: GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature 360:258, 1992

    Article  CAS  PubMed  Google Scholar 

  5. Romani N, Gruner S, Brang D, Kampgen E, Lenz A, Trockenbacher B, Konwalinka G, Fritsch P O, Steinman R M, Schuler G: Proliferating dendritic cell progenitors in human blood. J Exp Med 180:83, 1994

    CAS  PubMed  Google Scholar 

  6. Sallusto F, Lanzavecchia A: Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 179:1109, 1994

    Article  CAS  PubMed  Google Scholar 

  7. Boczkowski D, Nair SK, Snyder D, Gilboa E: Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J Exp Med 184:465, 1996

    Google Scholar 

  8. Celluzzi CM, Mayordomo JI, Storkus WJ, Lotze MT, Falo LD, Jr: Peptide-pulsed dendritic cells induce antigen-specific CTL-mediated protective tumor immunity (see comments). J Exp Med 183:283, 1996

    Article  CAS  PubMed  Google Scholar 

  9. Flamand V, Sornasse T, Thielemans K, Demanet C, Bakkus M, Bazin H, Tielemans F, Leo O, Urbain J, Moser M: Murine dendritic cells pulsed in vitro with tumor antigen induce tumor resistance in vivo. Eur J Immunol 24:605, 1994

    CAS  PubMed  Google Scholar 

  10. Zitvogel L, Mayordomo JI, Tjandrawan T, DeLeo AB, Clarke MR, Lotze MT, Storkus WJ: Therapy of murine tumors with tumor peptide-pulsed dendritic cells: Dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines (see comments). J Exp Med 183:87, 1996

    Google Scholar 

  11. Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B, Engleman EG, Levy R: Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med 2:52, 1996

    Article  CAS  PubMed  Google Scholar 

  12. Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G, Schadendorf D: Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 4:328, 1998

    CAS  PubMed  Google Scholar 

  13. Schuler-Thurner B, Dieckmann D, Keikavoussi P, Bender A, Maczek C, Jonuleit H, Roder C, Haendle I, Leisgang W, Dunbar R, Cerundolo V, von Den Driesch P, Knop J, Brocker EB, Enk A, Kampgen E, Schuler G: Mage-3 and influenza-matrix peptide-specific cytotoxic T cells are inducible in terminal stage HLA-A2.1+ melanoma patients by mature monocyte-derived dendritic cells. J Immunol 165:3492, 2000

    CAS  PubMed  Google Scholar 

  14. Mackensen A, Herbst B, Chen JL, Kohler G, Noppen C, Herr W, Spagnoli GC, Cerundolo V, Lindemann A: Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generated in vitro from CD34(+) hematopoietic progenitor cells. Int J Cancer 86:385, 2000

    Article  CAS  PubMed  Google Scholar 

  15. Geiger JD, Hutchinson RJ, Hohenkirk LF, McKenna EA, Yanik GA, Levine JE, Chang AE, Braun TM, Mule JJ: Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression. Cancer Res 61:8513, 2001

    CAS  PubMed  Google Scholar 

  16. Heiser A, Coleman D, Dannull J, Yancey D, Maurice MA, Lallas CD, Dahm P, Niedzwiecki D, Gilboa E, Vieweg J: Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Invest 109:409, 2002.

    Article  CAS  PubMed  Google Scholar 

  17. Banchereau J, Schuler-Thurner B, Palucka AK, Schuler G: Dendritic cells as vectors for therapy. Cell 106:271, 2001

    CAS  PubMed  Google Scholar 

  18. Banchereau J, Palucka AK, Dhodapkar M, Burkeholder S, Taquet N, Rolland A, Taquet S, Coquery S, Wittkowski KM, Bhardwaj N, Pineiro L, Steinman R, Fay J: Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. Cancer Res 61:6451, 2001

    CAS  PubMed  Google Scholar 

  19. Palucka AK, Dhodapkar MV, Paczesny S, Burkeholder S, Wittkowski KM, Steinman RM, Fay J, Banchereau J: Single injection of CD34+ progenitor-derived dendritic cell vaccine can lead to induction of T-cell immunity in patients with stage IV melanoma. J Immunother 26:432, 2003

    Article  CAS  PubMed  Google Scholar 

  20. Paczesny S, Banchereau J, Wittkowski KM, Saracino G, Fay J, Palucka AK: Expansion of Melanoma-specific Cytolytic CD8+ T Cell Precursors in Patients with Metastatic Melanoma Vaccinated with CD34+ Progenitor-derived Dendritic Cells. J Exp Med 199:1503, 2004

    Article  CAS  PubMed  Google Scholar 

  21. Stefanova I, Dorfman JR, Germain RN: Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature 420:429, 2002

    Article  CAS  PubMed  Google Scholar 

  22. Shedlock DJ, Shen H: Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300:337, 2003

    Article  CAS  PubMed  Google Scholar 

  23. Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP: CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421:852, 2003

    Article  CAS  PubMed  Google Scholar 

  24. Rocha B, Tanchot C: Towards a cellular definition of CD8+ T-cell memory: The role of CD4+ T-cell help in CD8+ T-cell responses. Curr Opin Immunol 16:259, 2004

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Baylor Institute for Immunology Research, Dallas, Texas

    A. Karolina Palucka, John Connolly, Hideki Ueno, John Kohl, Sophie Paczesny, Joseph Fay & Jacques Banchereau

  2. Laboratory of Tumor Immunology and Immunotherapy, Memorial Sloan Kettering Cancer Center, NY

    Madhav Dhodapkar

  3. Hematology Service, Memorial Sloan Kettering Cancer Center, NY

    Madhav Dhodapkar

  4. Baylor Institute for Immunology Research, 3434 Live Oak, Dallas, 75204, TX, USA

    A. Karolina Palucka

Authors
  1. A. Karolina Palucka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John Connolly
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hideki Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John Kohl
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sophie Paczesny
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Madhav Dhodapkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joseph Fay
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jacques Banchereau
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Palucka, A.K., Connolly, J., Ueno, H. et al. Spontaneous Proliferation and Type 2 Cytokine Secretion by CD4+T Cells in Patients with Metastatic Melanoma Vaccinated with Antigen-Pulsed Dendritic Cells. J Clin Immunol 25, 288–295 (2005). https://doi.org/10.1007/s10875-005-4089-z

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-005-4089-z

Key Words

Search

Navigation