Skip to main content

Advertisement

SpringerLink
Log in

Low expression of CD161 and NKG2D activating NK receptor is associated with impaired NK cell cytotoxicity in metastatic melanoma patients

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

Abstract

Natural killer (NK) cells play a role in the innate and adaptive antitumor immune responses. The activity of NK cells is regulated by functionally opposing, activating and inhibitory receptors whose balance ultimately determines whether target cells will be susceptible to NK cell mediated lysis. As melanoma is an immunogenic tumor, the effect of immunomodulating agents is consistently investigated. In this study in 79 metastatic melanoma (MM) patients and 52 controls NK activity, expression of activating NKG2D and CD161 receptors and KIR receptors, CD158a and CD158b, on freshly isolated PBL and NK cells were evaluated. Native NK cell activity of melanoma patients in clinical stage I–III and MM patients was determined against NK sensitive K562, NK resistant Daudi, human melanoma FemX, HeLa and HL 60 target tumor cell lines. In addition, predictive pretherapy immunomodulating effect after 18 h in vitro treatments of PBL of MM patients with rh IL-2, IFN-α (IFN), 13-cis retinoic acid (RA) and combination IFN-α and RA was evaluated with respect to NK cell lyses against K562 and FemX cell lines. In this study we show for the first time that low expression of CD161 and activating NKG2D receptors, without increased expression of KIR receptors CD158a and CD158b, as well as a decrease in the cytotoxic, CD16bright NK cell subset, is associated with a significant impairment in NK cell activity in MM patients. Furthermore, the predictive pretherapy finding that IL-2, IFN, IFN and RA, unlike RA alone, can enhance NK cell activity of MM patients against FemX melanoma tumor cell line can be of help in the design and development of therapeutic regimens, considering that it has recently been shown that low-dose combination of different immunomodulators represents the most promising approach in the therapy of MM.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

NK:

Natural killer cells

IL-2:

Interleukin-2

RA:

13-cis retinoic acid

FITC:

Fluorescein isothyocyanate

PE:

Phycoerythrine

KIR:

Killer immunoglobulin-like receptors

References

  1. Kiessling R, Klein E, Wigzell H (1975) “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol 5(2):112–117

    Article  PubMed  CAS  Google Scholar 

  2. Biron CA, Nguyen KB, Pien GC et al (1999) Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17:189–220

    Article  PubMed  CAS  Google Scholar 

  3. Lanier LL (1998) NK cell receptors. Annu Rev Immunol 16:359

    Article  PubMed  CAS  Google Scholar 

  4. Biassoni R, Cantoni C, Marras D et al (2003) Human natural killer cell receptors: insights into their molecular function and structure. J Cell Mol Med 7:376–387

    PubMed  CAS  Google Scholar 

  5. Smyth MJ, Swann J, Kelly JM et al (2004) NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer. J Exp Med 200(10):1325–1335

    Article  PubMed  CAS  Google Scholar 

  6. Rosen DB, Bettadapura J, Alsharifi M et al (2005) Cutting edge: lectin-like transcript-1 is a ligand for the inhibitory human NKR-P1A receptor. J Immunol 175(12):7796–7799

    PubMed  CAS  Google Scholar 

  7. Moretta A, Bottino C, Mingari MC et al (2002) What is a natural killer cell? Nat Immunol 3:6–8

    Article  PubMed  CAS  Google Scholar 

  8. Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22(11):633–640

    Article  PubMed  CAS  Google Scholar 

  9. Costello RT, Sivori S, Marcenaro E et al (2002) Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia. Blood 99(10):3661–3667

    Article  PubMed  CAS  Google Scholar 

  10. Konjevic G, Jurisic V, Banicevic B et al (1999) The difference in NK-cell activity between patients with non-Hodgkin’s lymphomas and Hodgkin’s disease. Br J Haematol 104(1):144–151

    Article  PubMed  CAS  Google Scholar 

  11. Konjevic G, Jovic V, Jurisic V et al (2003) 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-alpha and DTIC. Clin Exp Metastasis 20(7):647–655

    Article  PubMed  CAS  Google Scholar 

  12. Garbe C, Eigentler TK (2004) [Therapy of malignant melanoma at the stage of distant metastasis]. Hautarzt 55(2):195–213

    Article  PubMed  CAS  Google Scholar 

  13. Tarhini AA, Agarwala SS (2005) Interleukin-2 for the treatment of melanoma. Curr Opin Investig Drugs 6(12):1234–1239

    PubMed  CAS  Google Scholar 

  14. Rosenthal MA, Oratz R (1998) Phase II clinical trial of recombinant alpha 2b interferon and 13 cis retinoic acid in patients with metastatic melanoma. Am J Clin Oncol 21(4):352–354

    Article  PubMed  CAS  Google Scholar 

  15. Sidell N, Famatiga E, Shau H et al (1985) Immunological aspects of retinoids in humans. III. Effects of retinoic acid on the natural killing of tumor cells. J Biol Response Mod 4(3):240–250

    PubMed  CAS  Google Scholar 

  16. Labarriere N, Piau JP, Zennadi R et al (1993) Retinoic acid modulation of alpha (1,2) fucosyltransferase activity and sensitivity of tumor cells to LAK-mediated cytotoxicity. In Vitro Cell Dev Biol 29A(2):140–144

    PubMed  CAS  Google Scholar 

  17. Weber RW, O’Day S, Rose M et al (2005) Low-dose outpatient chemobiotherapy with temozolomide, granulocyte-macrophage colony stimulating factor, interferon-alpha2b, and recombinant interleukin-2 for the treatment of metastatic melanoma. J Clin Oncol 23(35):8992–9000

    Article  PubMed  CAS  Google Scholar 

  18. Jackson A., Warner N (1986) Preparation, staining and analysis by flow cytometry of peripheral blood leukocytes. In: Rose N, Friedmah H, Fahey J (eds) Manual of clinical laboratory immunology, 3rd edn. American Society for Microbiology, Washington DC, pp 226–335

    Google Scholar 

  19. Konjevic G, Jovic V, Radulovic S et al (2001) Therapeutic implications of the kinetics of immunomodulation during single or combined treatment of melanoma patients with dacarbazine and interferon-alpha. Neoplasma 48(3):175–181

    PubMed  CAS  Google Scholar 

  20. Brown RL, Ortaldo JR, Griffith RL et al (1985) The proliferation and function of human mononuclear leukocytes and natural killer cells in serum-free medium. J Immunol Methods 81(2):207–214

    Article  PubMed  CAS  Google Scholar 

  21. Robertson MJ, Ritz J (1990) Biology and clinical relevance of human natural killer cells. Blood 7:2421–2438

    Google Scholar 

  22. Konjevic G, Jurisic V, Spuzic I (2001) Association of NK cell dysfunction with changes in LDH characteristics of peripheral blood lymphocytes (PBL) in breast cancer patients. Breast Cancer Res Treat 66(3):255–263

    Article  PubMed  CAS  Google Scholar 

  23. Sun PD (2003) Structure and function of natural-killer-cell receptors. Immunol Res 27:539–548

    Article  PubMed  CAS  Google Scholar 

  24. Lee JC, Lee KM, Kim DW et al (2004) Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients J Immunol 172(12):7335–7340

    PubMed  CAS  Google Scholar 

  25. Konjevic G, Spuzic I (1997) Investigation of some factors that modulate the activity of NK cells. In: Lukic M, Colic M, Mostarica-Stojkovic M, Cuperlovic K (eds) Immunoregulation in health and disease. Academic Press, London pp 449–455

    Google Scholar 

  26. Seidel MG, Freissmuth M, Pehamberger H et al (1998) Stimulation of natural killer activity in peripheral blood lymphocytes of healthy donors and melanoma patients in vitro: synergism between interleukin (IL)-12 and IL-15 or IL-12 and IL-2. Naunyn Schmiedebergs Arch Pharmacol 358(3):382–389

    Article  PubMed  CAS  Google Scholar 

  27. Pende D, Parolini S, Pessino A et al (1999) Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J Exp Med 190:1505–1516

    Article  PubMed  CAS  Google Scholar 

  28. Yan Y, Steinherz P, Klingemann HG et al (1998) Antileukemia activity of a natural killer cell line against human leukemias. Clin Cancer Res 4(11):2859–2868

    PubMed  CAS  Google Scholar 

  29. Jovic V, Konjevic G, Radulovic S et al (2001) Impaired perforin-dependent NK cell cytotoxicity and proliferative activity of peripheral blood T cells is associated with metastatic melanoma. Tumori 87(5):324–329

    PubMed  CAS  Google Scholar 

  30. Pascal V, Schleinitz N, Brunet C et al (2004) Comparative analysis of NK cell subset distribution in normal and lymphoproliferative disease of granular lymphocyte conditions. Eur J Immunol 34:2930–2940

    Article  PubMed  CAS  Google Scholar 

  31. Moretta A, Bottino C, Vitale M et al (2001) Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 19:197–223

    Article  PubMed  CAS  Google Scholar 

  32. Dunne J, Lynch S, O’Farrelly C et al (2001) Selective expansion and partial activation of human NK cells and NK receptor-positive T cells by IL-2 and IL-15. J Immunol 167:3129–3138

    PubMed  CAS  Google Scholar 

  33. Andre P, Castriconi R, Espeli M et al (2004) Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors. Eur J Immunol 34:961–971

    Article  PubMed  CAS  Google Scholar 

  34. Bauer S, Groh V, Wu J et al (1999) Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285:727–729

    Article  PubMed  CAS  Google Scholar 

  35. Pende D, Cantoni C, Rivera P et al (2001) Role of NKG2D in tumor cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumors of nonepithelial origin. Eur J Immunol 31:1076–1086

    Article  PubMed  CAS  Google Scholar 

  36. Guerra N, Guillard M, Angevin E et al (2000) Killer inhibitory receptor (CD158b) modulates the lytic activity of tumor-specific T lymphocytes infiltrating renal cell carcinomas. Blood 95(9):2883–2889

    PubMed  CAS  Google Scholar 

  37. Cosman D, Mullberg J, Sutherland CL et al (2001) ULBPs, novel MHC class I-related molecules, binds to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14:123–133

    Article  PubMed  CAS  Google Scholar 

  38. Sutherland CL, Chalupny NJ, Schooley K et al (2002) UL16-binding proteins, novel MHC class I-related proteins, binds to NKG2D and activates multiple signaling pathways in primary NK cells. J Immunol 168:671–679

    PubMed  CAS  Google Scholar 

  39. Groh V, Wu J, Yee C et al (2002) Tumor-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419(6908):734–738

    Article  PubMed  CAS  Google Scholar 

  40. Gomez-Lozano N, Estefania E, Williams F et al (2005) The silent KIR3DP1 gene (CD158c) is transcribed and might encode a secreted receptor in a minority of humans, in whom the KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1 genes are duplicated. Eur J Immunol 35:16–24

    Article  PubMed  CAS  Google Scholar 

  41. Vitale M, Della Chiesa M, Carlomango S et al (2004) The small subset of CD56bright CD16- natural killer cells is selectively responsible for both cell proliferation and interferon-γ production upon inactivation with dendritic cells. Eur J Immunol 34:1715–1722

    Article  PubMed  CAS  Google Scholar 

  42. Huard B, Karlsson L, Triebel F (2001) KIR down-regulation on NK cells is associated with down-regulation of activating receptors and NK cell inactivation. Eur J Immunol 31:1728–1735

    Article  PubMed  CAS  Google Scholar 

  43. Kogure T, Fujinaga H, Niizawa A et al (1999) Killer-cell inhibitory receptors, CD158a/b, are upregulated by interleukin-2, but not interferon-gamma or interleukin-4. Mediators Inflamm 8:313–318

    Article  PubMed  CAS  Google Scholar 

  44. Kogure T, Mantani N, Goto H et al (2002) The effect of interleukin-15 on the expression of killer-cell immunoglobulin-like receptors on peripheral natural killer cells in human. Mediators Inflamm 11:219–224

    Article  PubMed  CAS  Google Scholar 

  45. Bakker AB, Phillips JH, Figdor CG et al (1998) Killer cell inhibitory receptors for MHC class I molecules regulate lysis of melanoma cells mediated by NK cells, gamma delta T cells, and antigen-specific CTL. J Immunol 160:5239–5245

    PubMed  CAS  Google Scholar 

  46. Nagler A, Lanier LL, Cwirla S et al (1989) Comparative studies of human FcRIII-positive and negative natural killer cells. J Immunol 143(10):3183–3191

    PubMed  CAS  Google Scholar 

  47. Igarashi T, Wynberg J, Srinivasan R et al (2004) Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells. Blood 104:170–177

    Article  PubMed  CAS  Google Scholar 

  48. Ortaldo JR, Mason A, Overton R (1986) Lymphokine-activated killer cells. Analysis of progenitors and effectors. J Exp Med 164(4):1193–1205

    Article  PubMed  CAS  Google Scholar 

  49. Kirkwood JM, Richards T, Zarour HM et al (2002) Immunomodulatory effects of high-dose and low-dose interferon alpha2b in patients with high-risk resected melanoma: the E2690 laboratory corollary of intergroup adjuvant trial E1690. Cancer 95(5):1101–1112

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by the grant of the Ministry of Science and Technology of the Republic of Serbia, number 1602. We wish to thank Mrs. Jasna Popovic Basic and Mrs. Mirjana Culafic for help and excellent technical work.

Author information

Authors and Affiliations

  1. Institute of Oncology and Radiology of Serbia, 14 Pasterova, 11000, Belgrade, Serbia and Montenegro

    Gordana Konjević, Katarina Mirjačić Martinović, Ana Vuletić, Viktor Jović, Nada Babović & Ivan Spužić

  2. Medical School, University of Belgrade, Belgrade, Serbia and Montenegro

    Gordana Konjević & Ivan Spužić

  3. Medical School, University of Kragujevac, Kragujevac, Serbia and Montenegro

    Vladimir Jurisić

Authors
  1. Gordana Konjević
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katarina Mirjačić Martinović
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ana Vuletić
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Viktor Jović
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vladimir Jurisić
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nada Babović
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. 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., Mirjačić Martinović, K., Vuletić, A. et al. Low expression of CD161 and NKG2D activating NK receptor is associated with impaired NK cell cytotoxicity in metastatic melanoma patients. Clin Exp Metastasis 24, 1–11 (2007). https://doi.org/10.1007/s10585-006-9043-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-006-9043-9

Keywords

Search

Navigation