Skip to main content

Advertisement

SpringerLink
Log in

IL-2-mediated augmentation of NK-cell activity and activation antigen expression on NK- and T-cell subsets in patients with metastatic melanoma treated with interferon-α and DTIC

  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Considering that well-defined and comprehensive immunological monitoring is the basis for the evaluation of the obtained immunmodulatory effects, we evaluated NK-cell activity, the number of CD3+CD4+, CD3+CD8+ T cells and CD16+CD56+ NK cells, as well as the expression of activation antigens, CD69, CD38 and HLA-DR on CD56+ NK cells, CD8+ and CD3+ T cells, simultaneously with IL-2 and TNF-α production, during chemoimmunotherapy with dacarbazine (DTIC) and interferon-α (IFN-α) in 39 patients with metastatic melanoma. In the first cycle of therapy, there was a significant rise in NK-cell activity, CD4+ T helper cell number, CD4/CD8 T-cell ratio, and the expression of activation antigens CD69 and CD38, on NK and T cells, respectively. However, in the following cycles there was a significant increase only in activation antigens without an increase in the percent or activity of NK cells. The early, but transient, immunopotentiation, present only in the first cycle of combined DTIC and IFN-α therapy, suggests that, in spite of increased IL-2 level, associated with augmented NK-cell activity, this therapy has a limited effect probably owing to the adverse effect of persistently high level of TNF-α in metastatic disease.

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. Biron CA, Cousens LP, Ruzek MC et al. Early cytokine responses to viral infections and their roles in shaping endogenous cellular immunity. Adv Exp Med Biol 1998; 452: 143–9.

    PubMed  CAS  Google Scholar 

  2. Hernberg M, Muhonen T, Pyrhönen S. Can the CD4+/CD8+ ratio predict the outcome of patients interferon-a therapy for renal cell carcinoma? Ann Oncol 1997; 8: 71–7.

    Article  PubMed  CAS  Google Scholar 

  3. Marrack P, Kappler, Mitchell T. Type I Interferons keep activated T cells alive. J Exp Med 1999; 189: 521–30.

    Article  PubMed  CAS  Google Scholar 

  4. Tompkins WA. Immunomodulation and therapeutic effects of the oral use of interferon-alpha: Mechanism of action. J Interferon Cytokine Res 1999; 19: 817–28.

    Article  PubMed  CAS  Google Scholar 

  5. Brittenden J, Heys SD, Ross J, Eremin O. Natural killer cells and cancer. Cancer 1996; 77: 1226–43.

    Article  PubMed  CAS  Google Scholar 

  6. Whiteside TI, Herberman RB. The role of natural killer cells in immune surveillance of cancer. Curr Opin Immnunol 1995; 7: 704–10.

    Article  CAS  Google Scholar 

  7. Deniz G, Akdis M, Aktas E et al. Human NK1 and NK2 subsets determined by purification of IFN-gamma-secreting and IFN-gammanon-secreting NK cells. Eur J Immunol 2002; 32: 879–84.

    Article  PubMed  CAS  Google Scholar 

  8. Yokoyama W.M. Natural killer cells. Right-side-up and up-side-down NK-cell receptors. Curr Biol 1995; 5: 982–5.

    Article  PubMed  CAS  Google Scholar 

  9. Kono K, Salazar-Onfray F, Petersson M et al. Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signaltransducing zeta molecules and inhibits tumor-specific T cell-and natural killer cell-mediated cytotoxicity. Eur J Immunol 1996; 26: 1308–13.

    PubMed  CAS  Google Scholar 

  10. Konjevic G, Jurisic V, Banicevic B, Spuzic I. The difference in NKcell activity between patients with non-Hodgkin's lymphomas and Hodgkin's disease. Br J Haematol 1999; 104: 144–51.

    Article  PubMed  CAS  Google Scholar 

  11. Kirkwood JM, Richards T, Zarour HM et al. Immunomodulatory effects of high-dose and low-dose interferon alpha 2b in patients with high risk resected melanoma: the E2690 laboratory corollary of inter group adjuvant trial E16 90. Cancer 2002; 95: 1101–12.

    Article  PubMed  CAS  Google Scholar 

  12. Borrego F, Kabat J, Kim DK et al. Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells. Mol Immunol, 2002; 38: 637–660.

    Article  PubMed  CAS  Google Scholar 

  13. Palmieri G, Morrone S, Lollini PL et al. TNF impairs in vivo and in vitro natural killer (NK) susceptibility of B16 melanoma cells. Scan J Immunol 1992; 35: 279–89.

    Article  CAS  Google Scholar 

  14. Ross ME, Caligiuri MA. Cytokine-induced apoptosis of human natural killer cells identifies a novel mechanism to regulate the innate immune response. Blood 1997; 89: 910–8.

    PubMed  CAS  Google Scholar 

  15. Falkson CI. Experience with interferon alpha 2b combined with dacarbazine in the treatment of metastatic malignant melanoma. Med Oncol 1995; 12: 35–40.

    Article  PubMed  CAS  Google Scholar 

  16. Roon IG, Inbar MJ, Gutman M et al. Recombinant interferon-2? in combination with dacarbazine in the treatment of metastaic malignant melanoma: Analysis of long-term responding patients. Cancer Immunol Immunother 1993; 37: 61–6.

    Article  Google Scholar 

  17. Hoffman MA, Wadler S. Mechanisms by which interferon potentiates chemotherapy. Cancer Invest 1993; 11: 310–13.

    PubMed  CAS  Google Scholar 

  18. Hernberg M, Muhonen T, Turunen JP et al. The CD4+/CD8+ ratio as a prognostic factor in patients treated with chemo-immunotherapy with metastatic melanoma. J Clin Oncol 1996; 14: 1690–6.

    PubMed  CAS  Google Scholar 

  19. Conti L, Arista MC, Callopoli A et al. Flow cytometry evaluation of lymphocytes subsets in non-treated neoplastic patients. J Clin Exp Cancer Res 1995; 5: 257–64.

    Google Scholar 

  20. Konjevic G, Jurisic V, Spuzic I. Correction to the original lactate dehydrogenase (LDH) release assay for evaluation of NK cell cytotoxicity. J Immunol Meth, 1997; 200: 199–201.

    Article  CAS  Google Scholar 

  21. Jurisic V, Spuzic I, Konjevic G. A comparison of NK cell activity with effects of TNF-alpha against K-562 cells, determined by LDH release assay. Cancer Lett 1999; 138: 67–72.

    Article  PubMed  CAS  Google Scholar 

  22. Johnston SR, Constenla DO, Moore J et al. Randomized phase II trial of BCDT [carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or without interferon alpha (IFN-alpha) and interleukin (IL-2) in patients with metastatic melanoma. Br J Cancer 1998; 77: 1280–6.

    PubMed  CAS  Google Scholar 

  23. Steinhauer EH, Doyle AT, Reed J, Kadish AS, Defective natural cytotoxicity in patients with cancer: Normal number of effector cells but decreased recycling capacity in patients with advanced disease. J Immunol 1982; 129: 2255–9.

    PubMed  CAS  Google Scholar 

  24. Zea AH, Curti BD, Longo DL et al. Alterations in T cell receptor and signal transduction molecules in melanoma patients. Clin Cancer Res 1995; 1: 1327–35.

    PubMed  CAS  Google Scholar 

  25. Kishi A, Ohmori M, Tomita S et al. Phenotypic and functional analyses of natural killer cells: Impaired NK activity partly due to the CD56+ cell dysfunction in cancer patients. Int J Immunother 1999; 15: 1–12.

    Google Scholar 

  26. Sibbit WL, Bankhurst AD, Jumonville AJ et al. Defects in natural killer activity and interferon response in human lung carcinoma and malignant melanoma. Cancer Res 1984; 44: 852–6.

    Google Scholar 

  27. Konjevic G, Jurisic V, Spuzic I. Association of NK cell dysfunction with changes in LDH characteristics of peripheral blood lymphocytes (PBL) in breast cancer patients. Breast Cancer Res Treat 2001; 66: 255–263

    Article  PubMed  CAS  Google Scholar 

  28. Krasagakis K, Tholke D, Farthmann B et al. Elevated plasma levels of transforming growth factor (TGF)-beta1 and TGF-beta2 in patients with disseminated malignant melanoma. Br J Cancer 1998; 77: 1492–4.

    PubMed  CAS  Google Scholar 

  29. Hafner M, Orosz P, Kruger A, Mannel DN. TNF promotes metastasis by impairing natural killer cell activity. Int J Cancer 1996; 66: 388–92.

    Article  PubMed  CAS  Google Scholar 

  30. Barlozzari, T, Leonhardt J, Wiltrout RH et al. Direct evidence for the role of LGL in the inhibition of experimental tumor metastases. J Immunol 1985; 134: 2783–9.

    PubMed  CAS  Google Scholar 

  31. Konjevic G, Spuzic I. Jurisic V. In-vitro effects of cytokines and cytokines receptors on the activity of NK cells. J BUON 1996; 1: 47–52.

    Google Scholar 

  32. Smyth MJ, Thia KY, Cretney E et al. Perforin is a major contributor to NK cell control of tumor metastasis. J Immunol 1999; 162: 6658–62.

    PubMed  CAS  Google Scholar 

  33. Campbell JJ, Qin S, Unutmaz D et al. Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire. J Immunol 2001; 166: 6477–82.

    PubMed  CAS  Google Scholar 

  34. Hersey P, Hasic E, Macdonald M et al. Effects of recombinant leukocyte interferon (rhIFN alpha A) on tumor growth and immune response in patients with metastatic melanoma. Br J Cancer 1985; 51: 815–26.

    PubMed  CAS  Google Scholar 

  35. Eisenthal A, Skornick Y, Ron I et al. Phenotypic and functional pro-file of peripheral blood mononuclear cells isolated from melanoma patients undergoing combined immunotherapy and chemotherapy. Cancer Immunol Immunother 1993; 37: 367–72.

    Article  PubMed  CAS  Google Scholar 

  36. Verhagen A, Mackay IR, Rowley M, Tymms M. Comparison of augmentation of human natural killer cell cytotoxicity by interferon-alpha subtypes. Nat Immun Cell Growth Regul 1990; 9: 325–33.

    PubMed  CAS  Google Scholar 

  37. Chakir H, Camilucci AA, Filion LG, Webb JR. Differentiation of murine NK cells into distinct subsets based on variable expression of the IL-12R beta 2 subunit. J Immunol 2000; 165: 4985–93.

    PubMed  CAS  Google Scholar 

  38. Konjevic G, Schlesinger B, Cheng L et al. Analysis of perforin expression in human peripheral blood lymphocytes, CD56+ natural killer cell subsets and its induction by interleukin-2. Immunol Invest 1995; 24: 499–507.

    PubMed  CAS  Google Scholar 

  39. Spaggiari GM, Contini P, Dondero A et al. Soluble HLA class I induces NK cell apoptosis upon the engagement of killer-activating HLA class I receptors through FasL-Fas interaction. Blood 2002; 100: 4098–107.

    Article  PubMed  CAS  Google Scholar 

  40. Golub SG, D'Amore PD, Rainey M. Systemic administration of human leukocyte interferon to melanoma patients. II. Cellular events associated with changes in natural killer cutotoxicity. J Nat Cancer Inst 1982; 68: 711–7.

    PubMed  CAS  Google Scholar 

  41. Mogensen KE, Lewerenz M, Reboul J et al. The type I interferon receptor: Structure, function, and evolution of a family business. J Interferon Cytokine Res 1999; 19: 1069–98.

    Article  PubMed  CAS  Google Scholar 

  42. Bajetta, E, Di Leo A, Zampino MG et al. Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma. J Clin Oncol, 1994; 12: 806–11.

    PubMed  CAS  Google Scholar 

  43. Atkins MB Immunotherapy and experimental approaches for metastatic melanoma. Melanoma 1998; 12: 877–902.

    CAS  Google Scholar 

  44. Aulitzky, WE, Aulitzky W, Gastl G et al. Acute effects of single dose of recombinant interferon-gamma on blood cell counts and lymphocyte subsets in patients with advanced renal cell cancer. J Interferon Res 1989; 9: 425–33.

    PubMed  CAS  Google Scholar 

  45. Testi R, D'ambrosio D, De Maria R, Santoni A. The CD69 receptor: Multipurpose cell surface trigger for hematopoietic cells. Immunol Today 1994; 15: 479–83.

    Article  PubMed  CAS  Google Scholar 

  46. Yacyshyn-Bowen, MB, Poppema S, Berg A et al. CD69+ and HLADR+ activation antigens on peripheral blood lymphocyte populations in metastatic breast and ovarian cancer patients: Correlation with survival following active specific immunotherapy. Int J Cancer 1995; 61: 470–4.

    Google Scholar 

  47. Simms PE, Ellis TM. Utility of flow cytometric detection of CD69 expression as a rapid method for determining poly-and oligoclonal lymphocyte activation. Clin Diag Lab Immunol 1996; 3: 301–4.

    CAS  Google Scholar 

  48. Borrego F, Robertson MJ, Ritz J et al. CD69 is a stimulatory receptor for natural killer cell and its cytotoxic effect is blocked by CD94 inhibitory receptor. J Immunol 1999; 97: 159–65.

    Article  CAS  Google Scholar 

  49. Pardoll DM, Topalian SL. The role of CD4 + T cell responses in antitumor immunity. Curr Opin Immunol 1998; 10: 588–94.

    Article  PubMed  CAS  Google Scholar 

  50. Hakansson A, Gustaffson B, Krysander L. et al. On down-regulation of the immune response to metastatic melanoma. Cancer Immunol Immunother 1999; 48: 253–62.

    Article  PubMed  CAS  Google Scholar 

  51. Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-?. Annu Rev Immunol 1997; 15: 749–95.

    Article  PubMed  CAS  Google Scholar 

  52. Surman DR, Mark ED, Overwijk WW, Restifol NP. Cutting edge: CD4+ T cell control of CD8+ T cell reactivity to a model tumor antigen. J Immunol 2000; 164: 562–5.

    PubMed  CAS  Google Scholar 

  53. Dobrzanski MJ, Reome JB, Dutton RW et al. Type 1 and type 2 CD8+ effectors T cell subpopulations promote long-term tumor immunity and protection to progressively growing tumor. Immunology 1999; 98: 535–40.

    Article  Google Scholar 

  54. Bernengo MG, Lisa F, Meregalli M et al. Changes in T and B lymphocyte subpoulations before, during and after chemotherapy for malignant melanoma. Int J Tissue React 1984; 6: 505–11.

    PubMed  CAS  Google Scholar 

  55. Pantaleo G, Koenig S, Baseler M et al. Defective clonogenic potential of CD8+ T-lymphocytes in patients with AIDS. Expansion in vivo of a non clonogenic CD3+CD8+DR+CD25-T cell population. J Immunol 1990; 144: 1696–704.

    PubMed  CAS  Google Scholar 

  56. Funaro A, De Monte LB, Dianzani U et al. Human CD38 is associated to distinct molecules which mediate transmembrane signaling in different lineages. Eur J Immunol 1993; 23: 2407–11.

    PubMed  CAS  Google Scholar 

  57. Mills CD, Kincaid K, Alt JM et al. M-1/M-2 Macrophages and the Th1/Th2 Paradigm. J Immunol 2000; 164: 6166–73.

    PubMed  CAS  Google Scholar 

  58. Degiannis D, Koniavitou K. In vitro expression of activation markers and lymphocyte proliferation in response to interleukin 12: Effect of immunosuppressive agents. Transpl Proc 1996; 28: 3062–4.

    CAS  Google Scholar 

  59. Reveneau S, Arnould L, Jolimoy G et al. Changes in sIL-6R and s TNF-Rs release by PMNs and the serum levels in breast cancer patients at different stages of treatment. Cytokine 1998; 79: 540–3.

    Google Scholar 

  60. Zoll B, Lefterova P, Ebert O et al. Modulation of cell surface markers on NK-like T lymphocytes by using IL-2, IL-7 or IL-12 in vitro stimulation. Cytokine 2000; 12: 1385–90.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute for Oncology and Radiology of Serbia, Belgrade, Yugoslavia

    Gordana Konjević, Viktor Jović, Siniša Radulović, Svetislav Jelić & Ivan Spužić

  2. School of Medicine, University of Belgrade, Belgrade, Yugoslavia

    Gordana Konjević & Ivan Spužić

  3. School of Medicine, University of Kragujevac, Serbia

    Vladimir Jurišić

Authors
  1. Gordana Konjević
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Viktor Jović
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vladimir Jurišić
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Siniša Radulović
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Svetislav Jelić
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ivan Spužić
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gordana Konjević.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Konjević, G., Jović, V., Jurišić, V. et al. IL-2-mediated augmentation of NK-cell activity and activation antigen expression on NK- and T-cell subsets in patients with metastatic melanoma treated with interferon-α and DTIC. Clin Exp Metastasis 20, 647–655 (2003). https://doi.org/10.1023/A:1027387930868

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1027387930868

Search

Navigation