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:

Immunology

NK resistance of tumor cells from multiple myeloma and chronic lymphocytic leukemia patients: implication of HLA-G

Leukemia volume 22, pages 998–1006 (2008)Cite this article

Abstract

Exploiting the antitumor effect of natural killer (NK) cells has regained interest in light of data from preclinical and clinical work on the potential of alloreactive NK cells. Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) represent the two most prevalent adult hematological malignancies in the western hemisphere. To evaluate the role of NK cells in the immune surveillance and their therapeutic potential for CLL and MM, tumor cell susceptibility to NK-mediated killing was investigated. Results show relative resistance of tumor cells from CLL as well as MM (73 and 70% of the patients, respectively) to NK-mediated killing. To gain insight into molecular mechanisms of this resistance, the expression of the tolerogenic HLA-G molecule in CLL and MM and its relevance to susceptibility to NK-mediated killing were investigated. HLA-G transcript was found in tumor cells from 89% (n=19) of CLL and 100% (n=9) of MM patients examined. HLA-G1 surface expression was observed in CLL and was very low or undetectable in MM. Notably, blocking of HLA-G1 with specific antibody on CLL samples increased their susceptibility to NK-mediated killing, demonstrating that HLA-G participates in protecting CLL cells from NK-mediated killing and may thus contribute to their immune escape in vivo.

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

Similar content being viewed by others

References

  1. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC . Advances in biology of multiple myeloma: clinical applications. Blood 2004; 104: 607–618.

    Article  CAS  Google Scholar 

  2. Hamblin TJ . Chronic lymphocytic leukaemia: clinical translations of biological features. Curr Top Microbiol Immunol 2005; 294: 165–185.

    CAS  Google Scholar 

  3. Hideshima T, Richardson P, Anderson KC . Novel therapeutic approaches for multiple myeloma. Immunol Rev 2003; 194: 164–176.

    Article  CAS  Google Scholar 

  4. Keating MJ, Chiorazzi N, Messmer B, Damle RN, Allen SL, Rai KR et al. Biology and treatment of chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program 2003, 153–175.

    Article  Google Scholar 

  5. Pant S, Copelan EA . Hematopoietic stem cell transplantation in multiple myeloma. Biol Blood Marrow Transplant 2007; 13: 877–885.

    Article  Google Scholar 

  6. Kharfan-Dabaja MA, Anasetti C, Santos ES . Hematopoietic cell transplantation for chronic lymphocytic leukemia: an evolving concept. Biol Blood Marrow Transplant 2007; 13: 373–385.

    Article  CAS  Google Scholar 

  7. Trinchieri G . Biology of natural killer cells. Adv Immunol 1989; 47: 187–376.

    Article  CAS  Google Scholar 

  8. Lanier LL . NK cell recognition. Annu Rev Immunol 2005; 23: 225–274.

    Article  CAS  Google Scholar 

  9. Lopez-Botet M, Llano M, Navarro F, Bellon T . NK cell recognition of non-classical HLA class I molecules. Semin Immunol 2000; 12: 109–119.

    Article  CAS  Google Scholar 

  10. Colonna M . Specificity and function of immunoglobulin superfamily NK cell inhibitory and stimulatory receptors. Immunol Rev 1997; 155: 127–133.

    Article  CAS  Google Scholar 

  11. Karre K . NK cells, MHC class I molecules and the missing self. Scand J Immunol 2002; 55: 221–228.

    Article  CAS  Google Scholar 

  12. Ruggeri L, Capanni M, Casucci M, Volpi I, Tosti A, Perruccio K et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood 1999; 94: 333–339.

    CAS  Google Scholar 

  13. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.

    Article  CAS  Google Scholar 

  14. Parham P, McQueen KL . Alloreactive killer cells: hindrance and help for haematopoietic transplants. Nat Rev Immunol 2003; 3: 108–122.

    Article  CAS  Google Scholar 

  15. Cosman D, Fanger N, Borges L, Kubin M, Chin W, Peterson L et al. A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Immunity 1997; 7: 273–282.

    Article  CAS  Google Scholar 

  16. Saverino D, Fabbi M, Ghiotto F, Merlo A, Bruno S, Zarcone D et al. The CD85/LIR-1/ILT-2 inhibitory receptor is expressed by all human T lymphocytes and down regulates their functions. J Immunol 2000; 165: 3742–3755.

    Article  CAS  Google Scholar 

  17. Rajagopalan S, Long EO . A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. J Exp Med 1999; 189: 1093–1100.

    Article  CAS  Google Scholar 

  18. Carosella ED, Moreau P, Le Maoult J, Le Discorde M, Dausset J, Rouas-Freiss N . HLA-G molecules: from maternal–fetal tolerance to tissue acceptance. Adv Immunol 2003; 81: 199–252.

    Article  CAS  Google Scholar 

  19. Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMars R . A class I antigen, HLA-G, expressed in human trophoblasts. Science 1990; 248: 220–223.

    Article  CAS  Google Scholar 

  20. King A, Hiby SE, Verma S, Burrows T, Gardner L, Loke YW . Uterine NK cells and trophoblast HLA class I molecules. Am J Reprod Immunol 1997; 37: 459–462.

    Article  CAS  Google Scholar 

  21. Rouas-Freiss N, Moreau P, Ferrone S, Carosella ED . HLA-G proteins in cancer: do they provide tumor cells with an escape mechanism? Cancer Res 2005; 65: 10139–10144.

    Article  CAS  Google Scholar 

  22. Paul P, Rouas-Freiss N, Khalil-Daher I, Moreau P, Riteau B, Le Gal FA et al. HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance. Proc Natl Acad Sci USA 1998; 95: 4510–4515.

    Article  CAS  Google Scholar 

  23. Wiendl H, Mitsdoerffer M, Hofmeister V, Wischhusen J, Bornemann A, Meyermann R et al. A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape. J Immunol 2002; 168: 4772–4780.

    Article  CAS  Google Scholar 

  24. Braud VM, Allan DS, O'Callaghan CA, Soderstrom K, D'Andrea A, Ogg GS et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 1998; 391: 795–799.

    Article  CAS  Google Scholar 

  25. LeMaoult J, Caumartin J, Daouya M, Favier B, Le Rond S, Gonzalez A et al. Immune regulation by pretenders: cell-to-cell transfers of HLA-G make effector T cells act as regulatory cells. Blood 2007; 109: 2040–2048.

    Article  CAS  Google Scholar 

  26. Caumartin J, Favier B, Daouya M, Guillard C, Moreau P, Carosella ED et al. Trogocytosis-based generation of suppressive NK cells. EMBO J 2007; 26: 1423–1433.

    Article  CAS  Google Scholar 

  27. Gong JH, Maki G, Klingemann HG . Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia 1994; 8: 652–658.

    CAS  Google Scholar 

  28. Maki G, Klingemann HG, Martinson JA, Tam YK . Factors regulating the cytotoxic activity of the human natural killer cell line, NK-92. J Hematother Stem Cell Res 2001; 10: 369–383.

    Article  CAS  Google Scholar 

  29. Lichtenfels R, Biddison WE, Schulz H, Vogt AB, Martin R . CARE-LASS (calcein-release-assay), an improved fluorescence-based test system to measure cytotoxic T lymphocyte activity. J Immunol Methods 1994; 172: 227–239.

    Article  CAS  Google Scholar 

  30. Liu L, Chahroudi A, Silvestri G, Wernett ME, Kaiser WJ, Safrit JT et al. Visualization and quantification of T cell-mediated cytotoxicity using cell-permeable fluorogenic caspase substrates. Nat Med 2002; 8: 185–189.

    Article  CAS  Google Scholar 

  31. Betts MR, Brenchley JM, Price DA, De Rosa SC, Douek DC, Roederer M et al. Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods 2003; 281: 65–78.

    Article  CAS  Google Scholar 

  32. Bryceson YT, March ME, Barber DF, Ljunggren HG, Long EO . Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells. J Exp Med 2005; 202: 1001–1012.

    Article  CAS  Google Scholar 

  33. Pierson BA, Miller JS . CD56+bright and CD56+dim natural killer cells in patients with chronic myelogenous leukemia progressively decrease in number, respond less to stimuli that recruit clonogenic natural killer cells, and exhibit decreased proliferation on a per cell basis. Blood 1996; 88: 2279–2287.

    CAS  Google Scholar 

  34. Costello RT, Sivori S, Marcenaro E, Lafage-Pochitaloff M, Mozziconacci MJ, Reviron D et al. Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia. Blood 2002; 99: 3661–3667.

    Article  CAS  Google Scholar 

  35. Kiladjian JJ, Bourgeois E, Lobe I, Braun T, Visentin G, Bourhis JH et al. Cytolytic function and survival of natural killer cells are severely altered in myelodysplastic syndromes. Leukemia 2006; 20: 463–470.

    Article  CAS  Google Scholar 

  36. Almeida J, Orfao A, Ocqueteau M, Mateo G, Corral M, Caballero MD et al. High-sensitive immunophenotyping and DNA ploidy studies for the investigation of minimal residual disease in multiple myeloma. Br J Haematol 1999; 107: 121–131.

    Article  CAS  Google Scholar 

  37. Le Gal FA, Riteau B, Sedlik C, Khalil-Daher I, Menier C, Dausset J et al. HLA-G-mediated inhibition of antigen-specific cytotoxic T lymphocytes. Int Immunol 1999; 11: 1351–1356.

    Article  CAS  Google Scholar 

  38. Menier C, Riteau B, Carosella ED, Rouas-Freiss N . MICA triggering signal for NK cell tumor lysis is counteracted by HLA-G1-mediated inhibitory signal. Int J Cancer 2002; 100: 63–70.

    Article  CAS  Google Scholar 

  39. Amiot L, Onno M, Drenou B, Monvoisin C, Fauchet R . HLA-G class I gene expression in normal and malignant hematopoietic cells. Hum Immunol 1998; 59: 524–528.

    Article  CAS  Google Scholar 

  40. Sebti Y, Le Friec G, Pangault C, Gros F, Drenou B, Guilloux V et al. Soluble HLA-G molecules are increased in lymphoproliferative disorders. Hum Immunol 2003; 64: 1093–1101.

    Article  CAS  Google Scholar 

  41. Polakova K, Krcova M, Kuba D, Russ G . Analysis of HLA-G expression in malignant hematopoetic cells from leukemia patients. Leuk Res 2003; 27: 643–648.

    Article  CAS  Google Scholar 

  42. Nuckel H, Rebmann V, Durig J, Duhrsen U, Grosse-Wilde H . HLA-G expression is associated with an unfavorable outcome and immunodeficiency in reb. Blood 2005; 105: 1694–1698.

    Article  Google Scholar 

  43. Leleu X, Le Friec G, Facon T, Amiot L, Fauchet R, Hennache B et al. Total soluble HLA class I and soluble HLA-G in multiple myeloma and monoclonal gammopathy of undetermined significance. Clin Cancer Res 2005; 11: 7297–7303.

    Article  CAS  Google Scholar 

  44. Apps R, Gardner L, Sharkey AM, Holmes N, Moffett A . A homodimeric complex of HLA-G on normal trophoblast cells modulates antigen-presenting cells via LILRB1. Eur J Immunol 2007; 37: 1924–1937.

    Article  CAS  Google Scholar 

  45. Gonen-Gross T, Achdout H, Arnon TI, Gazit R, Stern N, Horejsi V et al. The CD85J/Leukocyte inhibitory receptor-1 distinguishes between conformed and beta 2-microglobulin-free HLA-G molecules. J Immunol 2005; 175: 4866–4874.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by grants from ‘The Leukemia & Lymphoma Society’ and ‘Grant CLL-63119, Section of Hematology, Rush University Medical Center’.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Section of Hematology and Bone Marrow Transplantation, Rush University Medical Center, Chicago, IL, USA

    G Maki, G M Hayes, T Tyler & S A Gregory

  2. Service de Recherches en Hématologie-Immunologie, Commissariat a l'Energie Atomique, Hopital Saint-Louis, Paris, France

    G Maki, A Naji, E D Carosella & N Rouas-Freiss

Authors
  1. G Maki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G M Hayes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Naji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Tyler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E D Carosella
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N Rouas-Freiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S A Gregory
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G Maki.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maki, G., Hayes, G., Naji, A. et al. NK resistance of tumor cells from multiple myeloma and chronic lymphocytic leukemia patients: implication of HLA-G. Leukemia 22, 998–1006 (2008). https://doi.org/10.1038/leu.2008.15

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.15

Keywords

This article is cited by

Search

Advanced search

Quick links