Cancer Immunology, Immunotherapy

, Volume 63, Issue 1, pp 21–28 | Cite as

Advantages and clinical applications of natural killer cells in cancer immunotherapy

  • Erik Ames
  • William J. Murphy
Focussed Research Review


The past decade has witnessed a burgeoning of research and further insight into the biology and clinical applications of natural killer (NK) cells. Once thought to be simple innate cells important only as cytotoxic effector cells, our understanding of NK cells has grown to include memory-like responses, the guidance of adaptive responses, tissue repair, and a delicate paradigm for how NK cells become activated now termed “licensing” or “arming.” Although these cells were initially discovered and named for their spontaneous ability to kill tumor cells, manipulating NK cells in therapeutic settings has proved difficult and complex in part due to our emerging understanding of their biology. Therapies involving NK cells may either activate endogenous NK cells or involve transfers of exogenous cells by hematopoietic stem cell transplantation or adoptive cell therapy. Here, we review the basic biology of NK cells, highlighting characteristics which make NK cells particularly useful in cancer therapies. We also explore current treatment strategies that have been used for cancer as well as discuss potential future directions for the field.


NK cells HSCT Adoptive transfer Cytokines CITIM 2013 



The authors wish to thank Stephanie Mac, Can M. Sungur, Anthony E. Zamora, and Maite Alvarez for editing the manuscript and for helpful discussions. This work was funded in part by National Institutes of Health (NIH) Grant R01-HL089905.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Hallett WH, Murphy WJ (2006) Positive and negative regulation of natural killer cells: therapeutic implications. Semin Cancer Biol 16:367–382. doi: 10.1016/j.semcancer.2006.07.003 PubMedCrossRefGoogle Scholar
  2. 2.
    Bennett M (1987) Biology and genetics of hybrid resistance. Adv Immunol 41:333–445PubMedCrossRefGoogle Scholar
  3. 3.
    Bennett M (1973) Prevention of marrow allograft rejection with radioactive strontium: evidence for marrow-dependent effector cells. J Immunol 110:510–516PubMedGoogle Scholar
  4. 4.
    Herberman RB, Nunn ME, Lavrin DH (1975) Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity. Int J Cancer 16:216–229PubMedCrossRefGoogle Scholar
  5. 5.
    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 5:112–117. doi: 10.1002/eji.1830050208 PubMedCrossRefGoogle Scholar
  6. 6.
    Morandi B, Bougras G, Muller WA, Ferlazzo G, Munz C (2006) NK cells of human secondary lymphoid tissues enhance T cell polarization via IFN-gamma secretion. Eur J Immunol 36:2394–2400. doi: 10.1002/eji.200636290 PubMedCrossRefGoogle Scholar
  7. 7.
    Magri G, Muntasell A, Romo N et al (2011) NKp46 and DNAM-1 NK-cell receptors drive the response to human cytomegalovirus-infected myeloid dendritic cells overcoming viral immune evasion strategies. Blood 117:848–856. doi: 10.1182/blood-2010-08-301374 PubMedCrossRefGoogle Scholar
  8. 8.
    Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, Sallusto F (2004) Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol 5:1260–1265. doi: 10.1038/ni1138 PubMedCrossRefGoogle Scholar
  9. 9.
    Darmon AJ, Nicholson DW, Bleackley RC (1995) Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B. Nature 377:446–448. doi: 10.1038/377446a0 PubMedCrossRefGoogle Scholar
  10. 10.
    Barao I, Murphy WJ (2003) The immunobiology of natural killer cells and bone marrow allograft rejection. Biol Blood Marrow Transpl 9:727–741. doi: 10.1016/j.bbmt.2003.09.002 CrossRefGoogle Scholar
  11. 11.
    Kim S, Poursine-Laurent J, Truscott SM et al (2005) Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436:709–713. doi: 10.1038/nature03847 PubMedCrossRefGoogle Scholar
  12. 12.
    Sun K, Alvarez M, Ames E, Barao I, Chen M, Longo DL, Redelman D, Murphy WJ (2012) Mouse NK cell-mediated rejection of bone marrow allografts exhibits patterns consistent with Ly49 subset licensing. Blood 119:1590–1598. doi: 10.1182/blood-2011-08-374314 PubMedCrossRefGoogle Scholar
  13. 13.
    Tarek N, Le Luduec JB, Gallagher MM et al (2012) Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment. J Clin Invest 122:3260–3270. doi: 10.1172/JCI62749 PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Raulet DH, Vance RE (2006) Self-tolerance of natural killer cells. Nat Rev Immunol 6:520–531. doi: 10.1038/nri1863 PubMedCrossRefGoogle Scholar
  15. 15.
    Orr MT, Lanier LL (2010) Natural killer cell education and tolerance. Cell 142:847–856. doi: 10.1016/j.cell.2010.08.031 PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Jung H, Hsiung B, Pestal K, Procyk E, Raulet DH (2012) RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry. J Exp Med 209:2409–2422. doi: 10.1084/jem.20120565 PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Hershkovitz O, Rosental B, Rosenberg LA et al (2009) NKp44 receptor mediates interaction of the envelope glycoproteins from the West Nile and dengue viruses with NK cells. J Immunol 183:2610–2621. doi: 10.4049/jimmunol.0802806 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Garg A, Barnes PF, Porgador A et al (2006) Vimentin expressed on Mycobacterium tuberculosis-infected human monocytes is involved in binding to the NKp46 receptor. J Immunol 177:6192–6198PubMedGoogle Scholar
  19. 19.
    Lakshmikanth T, Burke S, Ali TH et al (2009) NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo. J Clin Invest 119:1251–1263. doi: 10.1172/JCI36022 PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Hallett WH, Ames E, Motarjemi M, Barao I, Shanker A, Tamang DL, Sayers TJ, Hudig D, Murphy WJ (2008) Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition. J Immunol 180:163–170PubMedGoogle Scholar
  21. 21.
    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 100:3633–3638. doi: 10.1182/blood-2001-12-0293 PubMedCrossRefGoogle Scholar
  22. 22.
    Curti A, Ruggeri L, D’Addio A et al (2011) Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood 118:3273–3279. doi: 10.1182/blood-2011-01-329508 PubMedCrossRefGoogle Scholar
  23. 23.
    Fabian A, Vereb G, Szollosi J (2013) The hitchhikers guide to cancer stem cell theory: markers, pathways and therapy. Cytometry A 83:62–71. doi: 10.1002/cyto.a.22206 PubMedCrossRefGoogle Scholar
  24. 24.
    Tallerico R, Todaro M, Di Franco S et al (2013) Human NK cells selective targeting of colon cancer-initiating cells: a role for natural cytotoxicity receptors and MHC class I molecules. J Immunol 190:2381–2390. doi: 10.4049/jimmunol.1201542 PubMedCrossRefGoogle Scholar
  25. 25.
    Jewett A, Tseng HC, Arasteh A, Saadat S, Christensen RE, Cacalano NA (2012) Natural killer cells preferentially target cancer stem cells; role of monocytes in protection against NK cell mediated lysis of cancer stem cells. Curr Drug Deliv 9:5–16PubMedCrossRefGoogle Scholar
  26. 26.
    Sutlu T, Alici E (2009) Natural killer cell-based immunotherapy in cancer: current insights and future prospects. J Intern Med 266:154–181. doi: 10.1111/j.1365-2796.2009.02121.x PubMedCrossRefGoogle Scholar
  27. 27.
    Rosenstein M, Ettinghausen SE, Rosenberg SA (1986) Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin 2. J Immunol 137:1735–1742PubMedGoogle Scholar
  28. 28.
    Meropol NJ, Porter M, Blumenson LE et al (1996) Daily subcutaneous injection of low-dose interleukin 2 expands natural killer cells in vivo without significant toxicity. Clin Cancer Res 2:669–677PubMedGoogle Scholar
  29. 29.
    Shevach EM (2000) Regulatory T cells in autoimmmunity*. Annu Rev Immunol 18:423–449. doi: 10.1146/annurev.immunol.18.1.423 PubMedCrossRefGoogle Scholar
  30. 30.
    Hallett WH, Ames E, Alvarez M, Barao I, Taylor PA, Blazar BR, Murphy WJ (2008) Combination therapy using IL-2 and anti-CD25 results in augmented natural killer cell-mediated antitumor responses. Biol Blood Marrow Transpl 14:1088–1099. doi: 10.1016/j.bbmt.2008.08.001 CrossRefGoogle Scholar
  31. 31.
    Malmberg KJ, Bryceson YT, Carlsten M et al (2008) NK cell-mediated targeting of human cancer and possibilities for new means of immunotherapy. Cancer Immunol Immunother 57:1541–1552. doi: 10.1007/s00262-008-0492-7 PubMedCrossRefGoogle Scholar
  32. 32.
    Ames E, Hallett WH, Murphy WJ (2009) Sensitization of human breast cancer cells to natural killer cell-mediated cytotoxicity by proteasome inhibition. Clin Exp Immunol 155:504–513. doi: 10.1111/j.1365-2249.2008.03818.x PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Welniak LA, Blazar BR, Murphy WJ (2007) Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 25:139–170. doi: 10.1146/annurev.immunol.25.022106.141606 PubMedCrossRefGoogle Scholar
  34. 34.
    Ruggeri L, Capanni M, Urbani E et al (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295:2097–2100. doi: 10.1126/science.1068440 PubMedCrossRefGoogle Scholar
  35. 35.
    Yu J, Venstrom JM, Liu XR, Pring J, Hasan RS, O’Reilly RJ, Hsu KC (2009) Breaking tolerance to self, circulating natural killer cells expressing inhibitory KIR for non-self HLA exhibit effector function after T cell-depleted allogeneic hematopoietic cell transplantation. Blood 113:3875–3884. doi: 10.1182/blood-2008-09-177055 PubMedCrossRefGoogle Scholar
  36. 36.
    Venstrom JM, Zheng J, Noor N et al (2009) KIR and HLA genotypes are associated with disease progression and survival following autologous hematopoietic stem cell transplantation for high-risk neuroblastoma. Clin Cancer Res 15:7330–7334. doi: 10.1158/1078-0432.CCR-09-1720 PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Dillman RO, Duma CM, Schiltz PM, DePriest C, Ellis RA, Okamoto K, Beutel LD, De Leon C, Chico S (2004) Intracavitary placement of autologous lymphokine-activated killer (LAK) cells after resection of recurrent glioblastoma. J Immunother 27:398–404PubMedCrossRefGoogle Scholar
  38. 38.
    Burns LJ, Weisdorf DJ, DeFor TE et al (2003) IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: a phase I/II trial. Bone Marrow Transpl 32:177–186. doi: 10.1038/sj.bmt.1704086 CrossRefGoogle Scholar
  39. 39.
    Miller JS, Soignier Y, Panoskaltsis-Mortari A et al (2005) Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105:3051–3057. doi: 10.1182/blood-2004-07-2974 PubMedCrossRefGoogle Scholar
  40. 40.
    Berg M, Lundqvist A, McCoy P Jr, Samsel L, Fan Y, Tawab A, Childs R (2009) Clinical-grade ex vivo-expanded human natural killer cells up-regulate activating receptors and death receptor ligands and have enhanced cytolytic activity against tumor cells. Cytotherapy 11:341–355. doi: 10.1080/14653240902807034 PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Esser R, Muller T, Stefes D et al (2012) NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. J Cell Mol Med 16:569–581. doi: 10.1111/j.1582-4934.2011.01343.x PubMedCrossRefGoogle Scholar
  42. 42.
    Li L, Liu LN, Feller S et al (2010) Expression of chimeric antigen receptors in natural killer cells with a regulatory-compliant non-viral method. Cancer Gene Ther 17:147–154. doi: 10.1038/cgt.2009.61 PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Muller T, Uherek C, Maki G, Chow KU, Schimpf A, Klingemann HG, Tonn T, Wels WS (2008) Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells. Cancer Immunol Immunother 57:411–423. doi: 10.1007/s00262-007-0383-3 PubMedCrossRefGoogle Scholar
  44. 44.
    Gong JH, Maki G, Klingemann HG (1994) Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia 8:652–658PubMedGoogle Scholar
  45. 45.
    Tam YK, Maki G, Miyagawa B, Hennemann B, Tonn T, Klingemann HG (1999) Characterization of genetically altered, interleukin 2-independent natural killer cell lines suitable for adoptive cellular immunotherapy. Hum Gene Ther 10:1359–1373. doi: 10.1089/10430349950018030 PubMedCrossRefGoogle Scholar
  46. 46.
    Arai S, Meagher R, Swearingen M, Myint H, Rich E, Martinson J, Klingemann H (2008) Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy 10:625–632. doi: 10.1080/14653240802301872 PubMedCrossRefGoogle Scholar
  47. 47.
    Cheng M, Ma J, Chen Y et al (2011) Establishment, characterization, and successful adaptive therapy against human tumors of NKG cell, a new human NK cell line. Cell Transpl 20:1731–1746. doi: 10.3727/096368911X580536 CrossRefGoogle Scholar
  48. 48.
    Khan KD, Emmanouilides C, Benson DM Jr et al (2006) A phase 2 study of rituximab in combination with recombinant interleukin-2 for rituximab-refractory indolent non-Hodgkin’s lymphoma. Clin Cancer Res 12:7046–7053. doi: 10.1158/1078-0432.CCR-06-1571 PubMedCrossRefGoogle Scholar
  49. 49.
    Jahn T, Zuther M, Friedrichs B, Heuser C, Guhlke S, Abken H, Hombach AA (2012) An IL12-IL2-antibody fusion protein targeting Hodgkin’s lymphoma cells potentiates activation of NK and T cells for an anti-tumor attack. PLoS One 7:e44482. doi: 10.1371/journal.pone.0044482 PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Chikamatsu K, Reichert TE, Kashii Y, Saito T, Kawashiri S, Yamamoto E, Whiteside TL (1999) Immunotherapy with effector cells and IL-2 of lymph node metastases of human squamous-cell carcinoma of the head and neck established in nude mice. Int J Cancer∝ 82:532–537CrossRefGoogle Scholar
  51. 51.
    O’Sullivan T, Saddawi-Konefka R, Vermi W et al (2012) Cancer immunoediting by the innate immune system in the absence of adaptive immunity. J Exp Med 209:1869–1882. doi: 10.1084/jem.20112738 PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    O’Sullivan T, Dunn GP, Lacoursiere DY, Schreiber RD, Bui JD (2011) Cancer immunoediting of the NK group 2D ligand H60a. J Immunol 187:3538–3545. doi: 10.4049/jimmunol.1100413 PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of DermatologyUC Davis School of MedicineSacramentoUSA

Personalised recommendations