Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

High Dose Chemotherapy

Impact of high-dose chemotherapy on antigen-specific T cell immunity in breast cancer patients. Application of new flow cytometric method

Bone Marrow Transplantation volume 29, pages 659–666 (2002)Cite this article

Abstract

The present study analyses the influence of high-dose chemotherapy (HD) and autologous stem cell transplantation on natural and vaccine-induced specific immunity in breast cancer patients. Peripheral blood was collected from five breast cancer patients at serial time points in connection with treatment and in a follow-up period of 1 year. The frequencies of CD8+ and CD4+ T cells responsive to cytomegalovirus (CMV), varicella zoster virus (VZV), and tetanus in antigen-activated whole blood were determined by flow cytometric analysis of CD69, TNFα, IFNγ and IL-4 expression. Mononuclear cells were labelled with PKH26 dye and the CMV, VZV, and tetanus toxoid-specific proliferation of T cell subpopulations was analysed by flow cytometry. In none of the patients did the treatment result in loss of overall T cell reactivity for any of the antigens. Prior to chemotherapy 5/5 patients possessed TNFα expressing T cells specific for CMV, 4/5 for VZV, and 3/5 for tetanus. One year after stem cell transplantation all patients possessed TNFα expressing T cells specific for CMV, VZV and tetanus. The highest percentages of cytokine-responding T cells were seen after stimulation with CMV antigen. In general, the lowest reactivity (close to zero) was measured in G-CSF-mobilised blood at the time of leukapheresis. In spite of a continuously reduced CD4 to CD8 ratio after transplantation, recovery of CD4+ T cells usually occurred prior to CD8+ recovery and often to a higher level. The study demonstrates that natural as well as vaccine-induced specific immunity established prior to HD can be regained after stem cell transplantation. These data indicate that introduction of a preventive cancer vaccination in combination with intensive chemotherapy may be a realistic treatment option.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Chakraborty N, Bilgrami S, Maness L et al. Myeloablative chemotherapy with autologous peripheral blood stem cell transplantation for metastatic breast cancer: immunologic consequences affecting clinical outcome Bone Marrow Transplant 1999 24: 837 843

    Article  CAS  PubMed  Google Scholar 

  2. Rutella S, Rumi C, Laurenti L et al. Immune reconstitution after transplantation of autologous peripheral CD34+ cells: analysis of predictive factors and comparison with unselected progenitor transplants Br J Haematol 2000 108: 105 115

    Article  CAS  PubMed  Google Scholar 

  3. Guillaume T, Rubinstein DB, Symann M . Immunological recovery and tumour-specific immunotherapeutic approaches to post-autologous haematopoietic stem cell transplantation Baillières Best Pract Res Clin Haematol 1999 12: 293 306

    Article  CAS  PubMed  Google Scholar 

  4. Mackall CL, Fleisher TA, Brown MR et al. Distinctions between CD8+ and CD4+ T-cell regenerative pathways result in prolonged T-cell subset imbalance after intensive chemotherapy Blood 1997 89: 3700 3707

    CAS  PubMed  Google Scholar 

  5. Koehne G, Zeller W, Stockschlaeder M, Zander AR . Phenotype of lymphocyte subsets after autologous peripheral blood stem cell transplantation Bone Marrow Transplant 1997 19: 149 156

    Article  CAS  PubMed  Google Scholar 

  6. Avigan D, Wu Z, Joyce R et al. Immune reconstitution following high-dose chemotherapy with stem cell rescue in patients with advanced breast cancer Bone Marrow Transplant 2000 26: 169 176

    Article  CAS  PubMed  Google Scholar 

  7. Guillaume T, Rubinstein DB, Symann M . Immune reconstitution and immunotherapy after autologous hematopoietic stem cell transplantation Blood 1998 92: 1471 1490

    CAS  PubMed  Google Scholar 

  8. Suni MA, Picker LJ, Maino VC . Detection of antigen-specific T cell cytokine expression in whole blood by flow cytometry J Immunol Meth 1998 212: 89 98

    Article  CAS  Google Scholar 

  9. Waldrop SL, Pitcher CJ, Peterson DM et al. Determination of antigen-specific memory/effector CD4+ T cell frequencies by flow cytometry: evidence for a novel, antigen-specific homeostatic mechanism in HIV-associated immunodeficiency J Clin Invest 1997 99: 1739 1750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Petrovsky N, Harrison LC . Cytokine-based human whole blood assay for the detection of antigen-reactive T cells J Immunol Methods 1995 186: 37 46

    Article  CAS  PubMed  Google Scholar 

  11. Nomura LE, Walker JM, Maecker HT . Optimization of whole blood antigen-specific cytokine assays for CD4(+) T cells Cytometry 2000 40: 60 68

    Article  CAS  PubMed  Google Scholar 

  12. Rostaing L, Tkaczuk J, Durand M et al. Kinetics of intracytoplasmic Th1 and Th2 cytokine production assessed by flow cytometry following in vitro activation of peripheral blood mononuclear cells Cytometry 1999 35: 318 328

    Article  CAS  PubMed  Google Scholar 

  13. Allsopp CE, Nicholls SJ, Langhorne J . A flow cytometric method to assess antigen-specific proliferative responses of different subpopulations of fresh and cryopreserved human peripheral blood mononuclear cells J Immunol Methods 1998 214: 175 186

    Article  CAS  PubMed  Google Scholar 

  14. Hellstrom I, Hellstrom KE . T cell immunity to tumor antigens Crit Rev Immunol 1998 18: 1 6

    Article  CAS  PubMed  Google Scholar 

  15. Knuth A, Wolfel T, Meyer zum Buschenfelde KH . T cell responses to human malignant tumours Cancer Surv 1992 13: 39 52

    CAS  PubMed  Google Scholar 

  16. Antman K, Ayash L, Elias A et al. A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy J Clin Oncol 1992 10: 102 110

    Article  CAS  PubMed  Google Scholar 

  17. Lanzavecchia A, Sallusto F . The instructive role of dendritic cells on T cell responses: lineages, plasticity and kinetics Curr Opin Immunol 2001 13: 291 298

    Article  CAS  PubMed  Google Scholar 

  18. Reid SD, Penna G, Adorini L . The control of T cell responses by dendritic cell subsets Curr Opin Immunol 2000 12: 114 121

    Article  CAS  PubMed  Google Scholar 

  19. Mielcarek M, Martin PJ, Torok-Storb B . Suppression of alloantigen-induced T-cell proliferation by CD14+ cells derived from granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells Blood 1997 89: 1629 1634

    CAS  PubMed  Google Scholar 

  20. Mielcarek M, Graf L, Johnson G, Torok-Storb B . Production of interleukin-10 by granulocyte colony-stimulating factor-mobilized blood products: a mechanism for monocyte-mediated suppression of T-cell proliferation Blood 1998 92: 215 222

    CAS  PubMed  Google Scholar 

  21. Tanaka J, Mielcarek M, Torok-Storb B . Impaired induction of the CD28-responsive complex in granulocyte colony-stimulating factor mobilized CD4 T cells Blood 1998 91: 347 352

    CAS  PubMed  Google Scholar 

  22. Thurner B, Roder C, Dieckmann D et al. Generation of large numbers of fully mature and stable dendritic cells from leukapheresis products for clinical application J Immunol Methods 1999 223: 1 15

    Article  CAS  PubMed  Google Scholar 

  23. Siena S, Di Nicola M, Bregni M et al. Massive ex vivo generation of functional dendritic cells from mobilized CD34+ blood progenitors for anticancer therapy Exp Hematol 1995 23: 1463 1471

    CAS  PubMed  Google Scholar 

  24. Choi D, Perrin M, Hoffmann S et al. Dendritic cell-based vaccines in the setting of peripheral blood stem cell transplantation: CD34+ cell-depleted mobilized peripheral blood can serve as a source of potent dendritic cells Clin Cancer Res 1998 4: 2709 2716

    CAS  PubMed  Google Scholar 

  25. Morse MA, Vredenburgh JJ, Lyerly HK . A comparative study of the generation of dendritic cells from mobilized peripheral blood progenitor cells of patients undergoing high-dose chemotherapy J Hematother Stem Cell Res 1999 8: 577 584

    Article  CAS  PubMed  Google Scholar 

  26. Galy A, Rudraraju S, Baynes R, Klein J . Recovery of lymphocyte and dendritic cell subsets after autologous CD34+ cell transplantation Bone Marrow Transplant 2000 25: 1249 1255

    Article  CAS  PubMed  Google Scholar 

  27. Steingrimsdottir H, Gruber A, Bjorkholm M et al. Immune reconstitution after autologous hematopoietic stem cell transplantation in relation to underlying disease, type of high-dose therapy and infectious complications Haematologica 2000 85: 832 838

    CAS  PubMed  Google Scholar 

  28. Reusser P, Fisher LD, Buckner CD, Thomas ED, Meyers JD . Cytomegalovirus infection after autologous bone marrow transplantation: occurrence of cytomegalovirus disease and effect on engraftment Blood 1990 75: 1888 1894

    CAS  PubMed  Google Scholar 

  29. Asanuma H, Sharp M, Maecker HT et al. Frequencies of memory T cells specific for varicella-zoster virus, herpes simplex virus, and cytomegalovirus by intracellular detection of cytokine expression J Infect Dis 2000 181: 859 866

    Article  CAS  PubMed  Google Scholar 

  30. Reusser P, Attenhofer R, Hebart H et al. Cytomegalovirus-specific T-cell immunity in recipients of autologous peripheral blood stem cell or bone marrow transplants Blood 1997 89: 3873 3879

    CAS  PubMed  Google Scholar 

  31. Schuchter LM, Wingard JR, Piantadosi S et al. Herpes zoster infection after autologous bone marrow transplantation Blood 1989 74: 1424 1427

    CAS  PubMed  Google Scholar 

  32. Bilgrami S, Chakraborty NG, Rodriguez-Pinero F et al. Varicella zoster virus infection associated with high-dose chemotherapy and autologous stem cell rescue Bone Marrow Transplant 1999 23: 469 474

    Article  CAS  PubMed  Google Scholar 

  33. Svane IM, Homburg KM, Kamby C et al. Acute and late toxicity following adjuvant high-dose chemotherapy for high-risk primary operable breast cancer (submitted)

  34. Wilson A, Sharp M, Koropchak CM et al. Subclinical varicella-zoster virus viremia, herpes zoster, and T lymphocyte immunity to varicella-zoster viral antigens after bone marrow transplantation J Infect Dis 1992 165: 119 126

    Article  CAS  PubMed  Google Scholar 

  35. Protheroe AS, Pickard C, Johnson PW et al. Persistence of clonal T-cell expansions following high-dose chemotherapy and autologous peripheral blood progenitor cell rescue Br J Haematol 2000 111: 766 773

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by grants from Michaelsen Fonden, Hœrslev-fonden and Dansk Kraeftforsknings Fond. We are also grateful for the financial support from Moltums Fond, Petrus Andersen Fond, Direktr JA Srensen og hustru EI Srensens Mindefond, P & A Simonsens Fond, G & A Haensch's Fond and Direktr J Madsen & hustru O Madsens Fond.

Author information

Authors and Affiliations

  1. Department of Oncology, Herlev Hospital/University of Copenhagen, Herlev, Denmark

    IM Svane, SW Hansen, C Kamby & DL Nielsen

  2. Department of Haematology, Herlev Hospital/University of Copenhagen, Herlev, Denmark

    K Nikolajsen & HE Johnsen

Authors
  1. IM Svane
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Nikolajsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. SW Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Kamby
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. DL Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. HE Johnsen
    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

Svane, I., Nikolajsen, K., Hansen, S. et al. Impact of high-dose chemotherapy on antigen-specific T cell immunity in breast cancer patients. Application of new flow cytometric method. Bone Marrow Transplant 29, 659–666 (2002). https://doi.org/10.1038/sj.bmt.1703521

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1703521

Keywords

Search

Advanced search

Quick links