Interleukin-15 enhances natural killer cell cytotoxicity in patients with acute myeloid leukemia by upregulating the activating NK cell receptors

  • Miroslaw J. Szczepanski
  • Marta Szajnik
  • Ann Welsh
  • Kenneth A. Foon
  • Theresa L. Whiteside
  • Michael BoyiadzisEmail author
Original Article


Interleukin-15 (IL-15) has a major role in NK-cell homeostasis. Modulation of the relative frequency and expression intensity of the NK-cell receptors by IL-15 may increase NK cell-mediated cytotoxicity in cancer patients. We investigated the receptor repertoire and measured NK-cell activity in newly diagnosed AML patients and evaluated the ex vivo effects of IL-15. The expression of the activating NK cell receptors was significantly decreased in the AML patients compared to that in NK cells of healthy donors. When NK cells obtained from AML patients were cultured with IL-15, expression of the activating receptors was significantly upregulated compared to pre-culture levels. Concomitantly, cytotoxic activity of NK cells against autologous leukemic blasts increased following IL-15 stimulation. This IL-15 induced increase in activity was blocked by neutralizing antibodies specific for the NK cell activating receptors. These pre-clinical data support the future use of IL-15 for NK cell- based therapies for AML patients.


Acute myeloid leukemia Natural killer cells Activating receptors NCRs NKG2D Interleukin -15 



This article was supported in part by Production Assistance for Cellular Therapies (PACT) under contract N01-HB-37165 from the NHLBI (TLW, MS), The Mario Lemieux Foundation (MB) and PO1-CA109688 from the NCI (TLW).

Conflict of interest statement

All authors agree with the contents of the manuscript and all authors declare that they have no conflict of interest.


  1. 1.
    Caligiuri MA (2008) Human natural killer cells. Blood 112:461–469CrossRefPubMedGoogle Scholar
  2. 2.
    Farag SS, Caligiuri MA (2006) Human natural killer cell development and biology. Blood Rev 20:123–137CrossRefPubMedGoogle Scholar
  3. 3.
    Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T (1999) Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285:727–729CrossRefPubMedGoogle Scholar
  4. 4.
    Cosman D, Mullberg J, Sutherland CL, Chin W, Armitage R, Fanslow W, Kubin M, Chalupny NJ (2001) ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14:123–133CrossRefPubMedGoogle Scholar
  5. 5.
    Gonzalez S, Groh V, Spies T (2006) Immunobiology of human NKG2D and its ligands. Curr Topics Microbiol Immunol 298:121–138CrossRefGoogle Scholar
  6. 6.
    Carbone E, Neri P, Mesuraca M, Fulciniti MT, Otsuki T, Pende D, Groh V, Spies T, Pollio G, Cosman D, Catalano L, Tassone P, Rotoli B, Venuta S (2005) HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood 105:251–258CrossRefPubMedGoogle Scholar
  7. 7.
    Pende D, Rivera P, Marcenaro S, Chang CC, Biassoni R, Conte R, Kubin M, Cosman D, Ferrone S, Moretta L, Moretta A (2002) Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Cancer Res 62:6178–6186PubMedGoogle Scholar
  8. 8.
    Vivier E, Nunes JA, Vely F (2004) Natural killer cell signaling pathways. Science 306:1517–1519CrossRefPubMedGoogle Scholar
  9. 9.
    Bryceson YT, March ME, Ljunggren HG, Long EO (2006) Activation, coactivation, and costimulation of resting human natural killer cells. Immuno Rev 214:73–91CrossRefGoogle Scholar
  10. 10.
    Costello RT, Sivori S, Marcenaro E, Lafage-Pochitaloff M, Mozziconacci MJ, Reviron D, Gastaut JA, Pende D, Olive D, Moretta A (2002) Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia. Blood 99:3661–3667CrossRefPubMedGoogle Scholar
  11. 11.
    Tajima F, Kawatani T, Endo A, Kawasaki H (1996) Natural killer cell activity and cytokine production as prognostic factors in adult acute leukemia. Leukemia 10:478–482PubMedGoogle Scholar
  12. 12.
    Fauriat C, Just-Landi S, Mallet F, Arnoulet C, Sainty D, Olive D, Costello RT (2007) Deficient expression of NCR in NK cells from acute myeloid leukemia: Evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction. Blood 109:323–330CrossRefPubMedGoogle Scholar
  13. 13.
    Fujisaki H, Kakuda H, Shimasaki N, Imai C, Ma J, Lockey T, Eldridge P, Leung WH, Campana D (2009) Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res 69(9):4010–4017CrossRefPubMedGoogle Scholar
  14. 14.
    Bryceson YT, March ME, Ljunggren HG, Long EO (2006) Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood 107(1):159–166CrossRefPubMedGoogle Scholar
  15. 15.
    Oberlies J, Watzl C, Giese T, Luckner C, Kropf P, Müller I, Ho AD, Munder M (2009) Regulation of NK cell function by human granulocyte arginase. J Immunol 182(9):5259–5267CrossRefPubMedGoogle Scholar
  16. 16.
    Carson WE, Fehniger TA, Haldar S, Eckhert K, Lindemann MJ, Lai CF, Croce CM, Baumann H, Caligiuri MA (1997) A potential role for interleukin-15 in the regulation of human natural killer cell survival. J Clin Invest 99:937–943CrossRefPubMedGoogle Scholar
  17. 17.
    Cooper MA, Bush JE, Fehniger TA, VanDeusen JB, Waite RE, Liu Y, Aguila HL, Caligiuri MA (2002) In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells. Blood 100:3633–3638CrossRefPubMedGoogle Scholar
  18. 18.
    Prlic M, Blazar BR, Farrar MA, Jameson SC (2003) In vivo survival and homeostatic proliferation of natural killer cells. J Exp Med 197:967–976CrossRefPubMedGoogle Scholar
  19. 19.
    Boyiadzis M, Memon S, Carson J, Allen K, Szczepanski MJ, Vance BA, Dean R, Bishop MR, Gress RE, Hakim FT (2008) Up-regulation of NK cell activating receptors following allogeneic hematopoietic stem cell transplantation under a lymphodepleting reduced intensity regimen is associated with elevated IL-15 levels. Biol Blood Marrow Transplant 14:290–300CrossRefPubMedGoogle Scholar
  20. 20.
    Whiteside TL, Bryant J, Day R, Herberman RB (1990) Natural killer cytotoxicity in the diagnosis of immune dysfunction: criteria for a reproducible assay. J Clin Lab Anal 4:102–114CrossRefPubMedGoogle Scholar
  21. 21.
    Romagnani C, Juelke K, Falco M, Morandi B, D’Agostino A, Costa R, Ratto G, Forte G, Carrega P, Lui G, Conte R, Strowig T, Moretta A, Munz C, Thiel A, Moretta L, Ferlazzo G (2007) CD56brightCD16 killer Ig-like receptor-NK cells display longer telomeres and acquire features of CD56dim NK cells upon activation. J Immunol 178:4947–4955PubMedGoogle Scholar
  22. 22.
    Nowbakht P, Ionescu MC, Rohner A, Kalberer CP, Rossy E, Mori L, Cosman D, DeLibero G, Wodnar-Filipowicz A (2005) Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias. Blood 105:3615–3622CrossRefPubMedGoogle Scholar
  23. 23.
    Groh V, Wu J, Yee C, Spies T (2002) Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419:734–738CrossRefPubMedGoogle Scholar
  24. 24.
    Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295:2097–2100CrossRefPubMedGoogle Scholar
  25. 25.
    Chik KW, Li K, Pong H, Shing MM, Li CK, Yuen PM (2003) Elevated serum interleukin-15 level in acute graft-versus-host disease after hematopoietic cell transplantation. J Pediatr Hematol Oncol 25:960–964CrossRefPubMedGoogle Scholar
  26. 26.
    Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, McKenna D, Le C, Defor TE, Burns LJ, Orchard PJ, Blazar BR, Wagner JE, Slungaard A, Weisdorf DJ, Okazaki IJ, McGlave PB (2005) Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105:3051–3057CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Miroslaw J. Szczepanski
    • 1
    • 2
  • Marta Szajnik
    • 1
  • Ann Welsh
    • 1
  • Kenneth A. Foon
    • 1
  • Theresa L. Whiteside
    • 1
    • 3
  • Michael Boyiadzis
    • 1
    Email author
  1. 1.Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Cancer Institute University of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Departments of Clinical Immunology and OtolaryngologyPoznan University of Medical SciencesPoznanPoland
  3. 3.Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghUSA

Personalised recommendations