Cancer Immunology, Immunotherapy

, Volume 65, Issue 4, pp 453–463 | Cite as

Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies?

  • Beatriz Sanchez-Correa
  • Carmen Campos
  • Alejandra Pera
  • Juan M. Bergua
  • Maria Jose Arcos
  • Helena Bañas
  • Javier G. Casado
  • Sara Morgado
  • Esther Duran
  • Rafael Solana
  • Raquel Tarazona
Symposium-in-writing paper

Abstract

Several age-associated changes in natural killer (NK) cell phenotype have been reported that contribute to the defective NK cell response observed in elderly patients. A remodelling of the NK cell compartment occurs in the elderly with a reduction in the output of immature CD56bright cells and an accumulation of highly differentiated CD56dim NK cells. Acute myeloid leukaemia (AML) is generally a disease of older adults. NK cells in AML patients show diminished expression of several activating receptors that contribute to impaired NK cell function and, in consequence, to AML blast escape from NK cell immunosurveillance. In AML patients, phenotypic changes in NK cells have been correlated with disease progression and survival. NK cell-based immunotherapy has emerged as a possibility for the treatment of AML patients. The understanding of age-associated alterations in NK cells is therefore necessary to define adequate therapeutic strategies in older AML patients.

Keywords

AML Ageing DNAM-1 NK cells NKp46 NKp30 

Abbreviations

AML

Acute myeloid leukaemia

AML-NK

Acute myeloid leukaemia patient NK cells

BiKEs

Bispecific killer engagers

CAR

Chimeric antigen receptor

CMV

Cytomegalovirus

DNAM-1

DNAX accessory molecule-1

HLA

Human leucocyte antigen

IL

Interleukin

ILCs

Innate lymphoid cells

IFN

Interferon

KIRs

Killer cell immunoglobulin-like receptors

LAK

Lymphokine-activated killer

LILRs

Leucocyte immunoglobulin-like receptors

MHC

Major histocompatibility complex

MICA

MHC class I-related protein A

MICB

MHC class I-related protein B

NCRs

Natural cytotoxicity receptors

NEACT

Non-engrafting alloreactive cellular therapy

NK

Natural killer

NKG2D

NK group 2, member D

PBMCs

Peripheral blood mononuclear cells

TNF

Tumour necrosis factor

TriKEs

Trispecific killer engagers

ULBP

UL-16 binding protein

References

  1. 1.
    Algarra I, Garcia-Lora A, Cabrera T, Ruiz-Cabello F, Garrido F (2004) The selection of tumor variants with altered expression of classical and nonclassical MHC class I molecules: implications for tumor immune escape. Cancer Immunol Immunother 53:904–910CrossRefPubMedGoogle Scholar
  2. 2.
    Almeida-Oliveira A, Smith-Carvalho M, Porto LC, Cardoso-Oliveira J, Ribeiro AS, Falcao RR, Abdelhay E, Bouzas LF, Thuler LC, Ornellas MH, Diamond HR (2011) Age-related changes in natural killer cell receptors from childhood through old age. Hum Immunol 72:319–329CrossRefPubMedGoogle Scholar
  3. 3.
    Artis D, Spits H (2015) The biology of innate lymphoid cells. Nature 517:293–301CrossRefPubMedGoogle Scholar
  4. 4.
    Bachanova V, Miller JS (2014) NK cells in therapy of cancer. Crit Rev Oncog 19:133–141CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Balducci L, Yates J (2000) General guidelines for the management of older patients with cancer. Oncology (Williston Park) 14:221–227Google Scholar
  6. 6.
    Borrego F, Alonso MC, Galiani MD, Carracedo J, Ramirez R, Ostos B, Pena J, Solana R (1999) NK phenotypic markers and IL2 response in NK cells from elderly people. Exp Gerontol 34:253–265CrossRefPubMedGoogle Scholar
  7. 7.
    Bottino C, Castriconi R, Pende D, Rivera P, Nanni M, Carnemolla B, Cantoni C, Grassi J, Marcenaro S, Reymond N, Vitale M, Moretta L, Lopez M, Moretta A (2003) Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med 198:557–567CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Braciak TA, Wildenhain S, Roskopf CC, Schubert IA, Fey GH, Jacob U, Hopfner KP, Oduncu FS (2013) NK cells from an AML patient have recovered in remission and reached comparable cytolytic activity to that of a healthy monozygotic twin mediated by the single-chain triplebody SPM-2. J Transl Med 11:289CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Caligiuri MA (2008) Human natural killer cells. Blood 112:461–469CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Camous X, Pera A, Solana R, Larbi A (2012) NK cells in healthy aging and age-associated diseases. J Biomed Biotechnol 2012:195956CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Campos C, Pera A, Lopez-Fernandez I, Alonso C, Tarazona R, Solana R (2014) Proinflammatory status influences NK cells subsets in the elderly. Immunol Lett 162:298–302CrossRefPubMedGoogle Scholar
  12. 12.
    Campos C, Pera A, Sanchez-Correa B, Alonso C, Lopez-Fernandez I, Morgado S, Tarazona R, Solana R (2014) Effect of age and CMV on NK cell subpopulations. Exp Gerontol 54:130–137CrossRefPubMedGoogle Scholar
  13. 13.
    Chidrawar SM, Khan N, Chan YL, Nayak L, Moss PA (2006) Ageing is associated with a decline in peripheral blood CD56bright NK cells. Immun Ageing 3:10CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    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
  15. 15.
    Curti A, Ruggeri L, D’Addio A, Bontadini A, Dan E, Motta MR, Trabanelli S, Giudice V, Urbani E, Martinelli G, Paolini S, Fruet F, Isidori A, Parisi S, Bandini G, Baccarani M, Velardi A, Lemoli RM (2011) Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood 118:3273–3279CrossRefPubMedGoogle Scholar
  16. 16.
    de Andrade LF, Smyth MJ, Martinet L (2014) DNAM-1 control of natural killer cells functions through nectin and nectin-like proteins. Immunol Cell Biol 92:237–244CrossRefPubMedGoogle Scholar
  17. 17.
    Derhovanessian E, Solana R, Larbi A, Pawelec G (2008) Immunity, ageing and cancer. Immun Ageing 5:11CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Di Lorenzo G, Balistreri CR, Candore G, Cigna D, Colombo A, Romano GC, Colucci AT, Gervasi F, Listi F, Potestio M, Caruso C (1999) Granulocyte and natural killer activity in the elderly. Mech Ageing Dev 108:25–38CrossRefPubMedGoogle Scholar
  19. 19.
    Erba HP (2015) Finding the optimal combination therapy for the treatment of newly diagnosed AML in older patients unfit for intensive therapy. Leuk Res 39:183–191CrossRefPubMedGoogle Scholar
  20. 20.
    Farag SS, VanDeusen JB, Fehniger TA, Caligiuri MA (2003) Biology and clinical impact of human natural killer cells. Int J Hematol 78:7–17CrossRefPubMedGoogle Scholar
  21. 21.
    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
  22. 22.
    Gayoso I, Sanchez-Correa B, Campos C, Alonso C, Pera A, Casado JG, Morgado S, Tarazona R, Solana R (2011) Immunosenescence of human natural killer cells. J Innate Immun 3:337–343CrossRefPubMedGoogle Scholar
  23. 23.
    Glienke W, Esser R, Priesner C, Suerth JD, Schambach A, Wels WS, Grez M, Kloess S, Arseniev L, Koehl U (2015) Advantages and applications of CAR-expressing natural killer cells. Front Pharmacol 6:21CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hayhoe RP, Henson SM, Akbar AN, Palmer DB (2010) Variation of human natural killer cell phenotypes with age: identification of a unique KLRG1-negative subset. Hum Immunol 71:676–681CrossRefPubMedGoogle Scholar
  25. 25.
    Hazeldine J, Lord JM (2013) The impact of ageing on natural killer cell function and potential consequences for health in older adults. Ageing Res Rev 12:1069–1078CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Herberman RB, Nunn ME, Holden HT, Lavrin DH (1975) Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int J Cancer 16:230–239CrossRefPubMedGoogle Scholar
  27. 27.
    Horton NC, Mathew PA (2015) NKp44 and natural cytotoxicity receptors as damage-associated molecular pattern recognition receptors. Front Immunol 6:31CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hudspeth K, Silva-Santos B, Mavilio D (2013) Natural cytotoxicity receptors: broader expression patterns and functions in innate and adaptive immune cells. Front Immunol 4:69CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jabbour EJ, Estey E, Kantarjian HM (2006) Adult acute myeloid leukemia. Mayo Clin Proc 81:247–260CrossRefPubMedGoogle Scholar
  30. 30.
    Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300CrossRefPubMedGoogle Scholar
  31. 31.
    Khaznadar Z, Henry G, Setterblad N, Agaugue S, Raffoux E, Boissel N, Dombret H, Toubert A, Dulphy N (2014) Acute myeloid leukemia impairs natural killer cells through the formation of a deficient cytotoxic immunological synapse. Eur J Immunol 44:3068–3080CrossRefPubMedGoogle Scholar
  32. 32.
    Kiessling R, Klein E, Pross H, Wigzell H (1975) “Natural” killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell. Eur J Immunol 5:117–121CrossRefPubMedGoogle Scholar
  33. 33.
    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 5:112–117CrossRefPubMedGoogle Scholar
  34. 34.
    Klingemann H (2015) Challenges of cancer therapy with natural killer cells. Cytotherapy 17:245–249CrossRefPubMedGoogle Scholar
  35. 35.
    Koch J, Steinle A, Watzl C, Mandelboim O (2013) Activating natural cytotoxicity receptors of natural killer cells in cancer and infection. Trends Immunol 34:182–191CrossRefPubMedGoogle Scholar
  36. 36.
    Krakow EF, Bergeron J, Lachance S, Roy DC, Delisle JS (2014) Harnessing the power of alloreactivity without triggering graft-versus-host disease: how non-engrafting alloreactive cellular therapy might change the landscape of acute myeloid leukemia treatment. Blood Rev 28:249–261CrossRefPubMedGoogle Scholar
  37. 37.
    Krishnaraj R (1997) Senescence and cytokines modulate the NK cell expression. Mech Ageing Dev 96:89–101CrossRefPubMedGoogle Scholar
  38. 38.
    Lanier LL (2008) Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 9:495–502CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Le Garff-Tavernier M, Beziat V, Decocq J, Siguret V, Gandjbakhch F, Pautas E, Debre P, Merle-Beral H, Vieillard V (2010) Human NK cells display major phenotypic and functional changes over the life span. Aging Cell 9:527–535CrossRefPubMedGoogle Scholar
  40. 40.
    Lichtenegger FS, Lorenz R, Gellhaus K, Hiddemann W, Beck B, Subklewe M (2014) Impaired NK cells and increased T regulatory cell numbers during cytotoxic maintenance therapy in AML. Leuk Res 38:964–969CrossRefPubMedGoogle Scholar
  41. 41.
    Lion E, Willemen Y, Berneman ZN, Van TV, Smits EL (2012) Natural killer cell immune escape in acute myeloid leukemia. Leukemia 26:2019–2026CrossRefPubMedGoogle Scholar
  42. 42.
    Ljunggren HG, Karre K (1990) In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol Today 11:237–244CrossRefPubMedGoogle Scholar
  43. 43.
    Ljunggren HG, Malmberg KJ (2007) Prospects for the use of NK cells in immunotherapy of human cancer. Nat Rev Immunol 7:329–339CrossRefPubMedGoogle Scholar
  44. 44.
    Locatelli F, Moretta F, Brescia L, Merli P (2014) Natural killer cells in the treatment of high-risk acute leukaemia. Semin Immunol 26:173–179CrossRefPubMedGoogle Scholar
  45. 45.
    Lopez-Botet M, Muntasell A, Vilches C (2014) The CD94/NKG2C + NK-cell subset on the edge of innate and adaptive immunity to human cytomegalovirus infection. Semin Immunol 26:145–151CrossRefPubMedGoogle Scholar
  46. 46.
    Lutz CT, Moore MB, Bradley S, Shelton BJ, Lutgendorf SK (2005) Reciprocal age related change in natural killer cell receptors for MHC class I. Mech Ageing Dev 126:722–731CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Mariani E, Mariani AR, Meneghetti A, Tarozzi A, Cocco L, Facchini A (1998) Age-dependent decreases of NK cell phosphoinositide turnover during spontaneous but not Fc-mediated cytolytic activity. Int Immunol 10:981–989CrossRefPubMedGoogle Scholar
  48. 48.
    Mariani E, Meneghetti A, Neri S, Ravaglia G, Forti P, Cattini L, Facchini A (2002) Chemokine production by natural killer cells from nonagenarians. Eur J Immunol 32:1524–1529CrossRefPubMedGoogle Scholar
  49. 49.
    Miller JS (2013) Therapeutic applications: natural killer cells in the clinic. Hematol Am Soc Hematol Educ Prog 2013:247–253CrossRefGoogle Scholar
  50. 50.
    Milush JM, Lopez-Verges S, York VA, Deeks SG, Martin JN, Hecht FM, Lanier LL, Nixon DF (2013) CD56negCD16(+) NK cells are activated mature NK cells with impaired effector function during HIV-1 infection. Retrovirology 10:158CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Mocchegiani E, Malavolta M (2004) NK and NKT cell functions in immunosenescence. Aging Cell 3:177–184CrossRefPubMedGoogle Scholar
  52. 52.
    Montaldo E, Del ZG, Della CM, Mingari MC, Moretta A, De MA, Moretta L (2013) Human NK cell receptors/markers: a tool to analyze NK cell development, subsets and function. Cytometry A 83:702–713CrossRefPubMedGoogle Scholar
  53. 53.
    Montaldo E, Vacca P, Moretta L, Mingari MC (2014) Development of human natural killer cells and other innate lymphoid cells. Semin Immunol 26:107–113CrossRefPubMedGoogle Scholar
  54. 54.
    Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, Biassoni R, Moretta L (2001) Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 19:197–223CrossRefPubMedGoogle Scholar
  55. 55.
    Moretta L, Montaldo E, Vacca P, Del ZG, Moretta F, Merli P, Locatelli F, Mingari MC (2014) Human natural killer cells: origin, receptors, function, and clinical applications. Int Arch Allergy Immunol 164:253–264CrossRefPubMedGoogle Scholar
  56. 56.
    Muntasell A, Vilches C, Angulo A, Lopez-Botet M (2013) Adaptive reconfiguration of the human NK-cell compartment in response to cytomegalovirus: a different perspective of the host-pathogen interaction. Eur J Immunol 43:1133–1141CrossRefPubMedGoogle Scholar
  57. 57.
    Murasko DM, Jiang J (2005) Response of aged mice to primary virus infections. Immunol Rev 205:285–296CrossRefPubMedGoogle Scholar
  58. 58.
    Nowbakht P, Ionescu MC, Rohner A, Kalberer CP, Rossy E, Mori L, Cosman D, De LG, 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
  59. 59.
    Oyer JL, Igarashi RY, Kulikowski AR, Colosimo DA, Solh MM, Zakari A, Khaled YA, Altomare DA, Copik AJ (2015) Generation of highly cytotoxic natural killer cells for treatment of acute myelogenous leukemia using a feeder-free, particle-based approach. Biol Blood Marrow Transplant 21:632–639CrossRefPubMedGoogle Scholar
  60. 60.
    Pawelec G, Solana R (2008) Are cancer and ageing different sides of the same coin? conference on cancer and ageing. EMBO Rep 9:234–238CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Pawelec G, Solana R, Remarque E, Mariani E (1998) Impact of aging on innate immunity. J Leukoc Biol 64:703–712PubMedGoogle Scholar
  62. 62.
    Pende D, Spaggiari GM, Marcenaro S, Martini S, Rivera P, Capobianco A, Falco M, Lanino E, Pierri I, Zambello R, Bacigalupo A, Mingari MC, Moretta A, Moretta L (2005) Analysis of the receptor-ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the Poliovirus receptor (CD155) and Nectin-2 (CD112). Blood 105:2066–2073CrossRefPubMedGoogle Scholar
  63. 63.
    Rambaldi A, Biagi E, Bonini C, Biondi A, Introna M (2015) Cell-based strategies to manage leukemia relapse: efficacy and feasibility of immunotherapy approaches. Leukemia 29:1–10CrossRefPubMedGoogle Scholar
  64. 64.
    Raulet DH, Gasser S, Gowen BG, Deng W, Jung H (2013) Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol 31:413–441CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Romee R, Foley B, Lenvik T, Wang Y, Zhang B, Ankarlo D, Luo X, Cooley S, Verneris M, Walcheck B, Miller J (2013) NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood 121:3599–3608CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Salih HR, Antropius H, Gieseke F, Lutz SZ, Kanz L, Rammensee HG, Steinle A (2003) Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood 102:1389–1396CrossRefPubMedGoogle Scholar
  67. 67.
    Sanchez CJ, Le TT, Boehrer A, Knoblauch B, Imbert J, Olive D, Costello RT (2011) Natural killer cells and malignant haemopathies: a model for the interaction of cancer with innate immunity. Cancer Immunol Immunother 60:1–13CrossRefPubMedGoogle Scholar
  68. 68.
    Sanchez-Correa B, Bergua JM, Campos C, Gayoso I, Arcos MJ, Banas H, Morgado S, Casado JG, Solana R, Tarazona R (2013) Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels. Cytokine 61:885–891CrossRefPubMedGoogle Scholar
  69. 69.
    Sanchez-Correa B, Gayoso I, Bergua JM, Casado JG, Morgado S, Solana R, Tarazona R (2012) Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients. Immunol Cell Biol 90:109–115CrossRefPubMedGoogle Scholar
  70. 70.
    Sanchez-Correa B, Morgado S, Gayoso I, Bergua JM, Casado JG, Arcos MJ, Bengochea ML, Duran E, Solana R, Tarazona R (2011) Human NK cells in acute myeloid leukaemia patients: analysis of NK cell-activating receptors and their ligands. Cancer Immunol Immunother 60:1195–1205CrossRefPubMedGoogle Scholar
  71. 71.
    Schmeel FC, Schmeel LC, Gast SM, Schmidt-Wolf IG (2014) Adoptive immunotherapy strategies with cytokine-induced killer (CIK) cells in the treatment of hematological malignancies. Int J Mol Sci 15:14632–14648CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Shibuya A, Campbell D, Hannum C, Yssel H, Franz-Bacon K, McClanahan T, Kitamura T, Nicholl J, Sutherland GR, Lanier LL, Phillips JH (1996) DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 4:573–581CrossRefPubMedGoogle Scholar
  73. 73.
    Siegler U, Kalberer CP, Nowbakht P, Sendelov S, Meyer-Monard S, Wodnar-Filipowicz A (2005) Activated natural killer cells from patients with acute myeloid leukemia are cytotoxic against autologous leukemic blasts in NOD/SCID mice. Leukemia 19:2215–2222CrossRefPubMedGoogle Scholar
  74. 74.
    Solana R, Alonso MC, Pena J (1999) Natural killer cells in healthy aging. Exp Gerontol 34:435–443CrossRefPubMedGoogle Scholar
  75. 75.
    Solana R, Campos C, Pera A, Tarazona R (2014) Shaping of NK cell subsets by aging. Curr Opin Immunol 29:56–61CrossRefPubMedGoogle Scholar
  76. 76.
    Solana R, Mariani E (2000) NK and NK/T cells in human senescence. Vaccine 18:1613–1620CrossRefPubMedGoogle Scholar
  77. 77.
    Solana R, Pawelec G, Tarazona R (2006) Aging and innate immunity. Immunity 24:491–494CrossRefPubMedGoogle Scholar
  78. 78.
    Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T (2012) Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol 24:331–341CrossRefPubMedGoogle Scholar
  79. 79.
    Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Koyasu S, Locksley RM, McKenzie AN, Mebius RE, Powrie F, Vivier E (2013) Innate lymphoid cells–a proposal for uniform nomenclature. Nat Rev Immunol 13:145–149CrossRefPubMedGoogle Scholar
  80. 80.
    Stringaris K, Sekine T, Khoder A, Alsuliman A, Razzaghi B, Sargeant R, Pavlu J, Brisley G, de Lavallade H, Sarvaria A, Marin D, Mielke S, Apperley JF, Shpall EJ, Barrett AJ, Rezvani K (2014) Leukemia-induced phenotypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia. Haematologica 99:836–847CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Szczepanski MJ, Szajnik M, Welsh A, Foon KA, Whiteside TL, Boyiadzis M (2010) Interleukin-15 enhances natural killer cell cytotoxicity in patients with acute myeloid leukemia by upregulating the activating NK cell receptors. Cancer Immunol Immunother 59:73–79CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Tarazona R, Casado JG, Delarosa O, Torre-Cisneros J, Villanueva JL, Sanchez B, Galiani MD, Gonzalez R, Solana R, Pena J (2002) Selective depletion of CD56(dim) NK cell subsets and maintenance of CD56(bright) NK cells in treatment-naive HIV-1-seropositive individuals. J Clin Immunol 22:176–183CrossRefPubMedGoogle Scholar
  83. 83.
    Terme M, Ullrich E, Delahaye NF, Chaput N, Zitvogel L (2008) Natural killer cell-directed therapies: moving from unexpected results to successful strategies. Nat Immunol 9:486–494CrossRefPubMedGoogle Scholar
  84. 84.
    Verheyden S, Demanet C (2008) NK cell receptors and their ligands in leukemia. Leukemia 22:249–257CrossRefPubMedGoogle Scholar
  85. 85.
    Wiernik A, Foley B, Zhang B, Verneris MR, Warlick E, Gleason MK, Ross JA, Luo X, Weisdorf DJ, Walcheck B, Vallera DA, Miller JS (2013) Targeting natural killer cells to acute myeloid leukemia in vitro with a CD16 x 33 bispecific killer cell engager and ADAM17 inhibition. Clin Cancer Res 19:3844–3855CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Zafirova B, Wensveen FM, Gulin M, Polic B (2011) Regulation of immune cell function and differentiation by the NKG2D receptor. Cell Mol Life Sci 68:3519–3529CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Zhou Q, Gil-Krzewska A, Peruzzi G, Borrego F (2013) Matrix metalloproteinases inhibition promotes the polyfunctionality of human natural killer cells in therapeutic antibody-based anti-tumour immunotherapy. Clin Exp Immunol 173:131–139CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Beatriz Sanchez-Correa
    • 1
  • Carmen Campos
    • 2
  • Alejandra Pera
    • 2
  • Juan M. Bergua
    • 3
  • Maria Jose Arcos
    • 3
  • Helena Bañas
    • 3
  • Javier G. Casado
    • 1
    • 4
  • Sara Morgado
    • 1
  • Esther Duran
    • 5
  • Rafael Solana
    • 2
  • Raquel Tarazona
    • 1
  1. 1.Immunology UnitUniversity of ExtremaduraCáceresSpain
  2. 2.Department of Immunology, IMIBICReina Sofia University Hospital, University of CordobaCórdobaSpain
  3. 3.Department of HematologyHospital San Pedro de AlcantaraCáceresSpain
  4. 4.Stem Cell Therapy UnitMinimally Invasive Surgery Centre Jesus UsonCáceresSpain
  5. 5.Histology and Pathology Unit, Faculty of VeterinaryUniversity of ExtremaduraCáceresSpain

Personalised recommendations