Springer Seminars in Immunopathology

, Volume 27, Issue 1, pp 49–64 | Cite as

The role of natural killer cells in tumor control—effectors and regulators of adaptive immunity

Original Article


Natural killer (NK) cells are the primary effector cells of the innate immune system and have a well-established role in tumor rejection in a variety of spontaneous and induced cancer models. NK cell function is regulated by a complex balance of inhibitory and activating signals that allow them to selectively target and kill cells that display an abnormal pattern of cell surface molecules, while leaving normal healthy cells unharmed. In this review we discuss NK cell function, the role of NK cells in cancer therapies, the emerging concept of bi-directional cross-talk between NK cells and dendritic cells, and the implications of these interactions for tumor immunotherapy.


Immunotherapy Immunosurveillance Cytokine Cytotoxicity Dendritic cells 


  1. 1.
    Ballas ZK, Turner JM, Turner DA, et al (1990) A patient with simultaneous absence of “classical” natural killer cells (CD3, CD16+, and NKH1+) and expansion of CD3+, CD4, CD8, NKH1+ subset. J Allergy Clin Immunol 85:453Google Scholar
  2. 2.
    Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245Google Scholar
  3. 3.
    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 285:727Google Scholar
  4. 4.
    Bennett IM, Zatsepina O, Zamai L, et al (1996) Definition of a natural killer NKR-P1A+/CD56/CD16 functionally immature human NK cell subset that differentiates in vitro in the presence of interleukin 12. J Exp Med, 184:1845Google Scholar
  5. 5.
    Borrego F, Kabat J, Kim DK, et al (2002) Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells. Mol Immunol 38:637Google Scholar
  6. 6.
    Brady J, Hayakawa Y, Smyth MJ, et al (2004) IL-21 induces the functional maturation of murine NK cells. J Immunol 172:2048Google Scholar
  7. 7.
    Buentke E, Heffler LC, Wilson JL, et al (2002) Natural killer and dendritic cell contact in lesional atopic dermatitis skin—Malassezia-influenced cell interaction. J Invest Dermatol 119:850Google Scholar
  8. 8.
    Campbell JJ, Qin S, Unutmaz D, et al (2001) Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire. J Immunol 166:6477Google Scholar
  9. 9.
    Cerwenka A, Baron JL, Lanier LL (2001) Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc Natl Acad Sci USA 98:11521Google Scholar
  10. 10.
    Cerwenka A, Lanier LL (2001) Ligands for natural killer cell receptors: redundancy or specificity. Immunol Rev 181:158Google Scholar
  11. 11.
    Cerwenka A, Lanier LL (2001) Natural killer cells, viruses and cancer. Nat Rev Immunol 1:41Google Scholar
  12. 12.
    Chalifour A, Jeannin P, Gauchat JF, et al (2004) Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers α-defensin production. Blood 104:1778Google Scholar
  13. 13.
    Colucci F, Caligiuri MA, Di Santo JP (2003) What does it take to make a natural killer? Nat Rev Immunol 3:413Google Scholar
  14. 14.
    Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22:633Google Scholar
  15. 15.
    Cooper MA, Fehniger TA, Fuchs A, et al (2004) NK cell and DC interactions. Trends Immunol 25:47Google Scholar
  16. 16.
    Cretney E, Takeda K, Yagita H, et al (2002) Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 168:1356Google Scholar
  17. 17.
    Cui Z, Willingham MC, Hicks AM, et al (2003) Spontaneous regression of advanced cancer: identification of a unique genetically determined, age-dependent trait in mice. Proc Natl Acad Sci USA 100:6682Google Scholar
  18. 18.
    Davis JE, Smyth MJ, Trapani JA (2001) Granzyme A and B-deficient killer lymphocytes are defective in eliciting DNA fragmentation but retain potent in vivo anti-tumor capacity. Eur J Immunol 31:39Google Scholar
  19. 19.
    Della Chiesa M, Vitale M, Carlomagno S, et al (2003) The natural killer cell-mediated killing of autologous dendritic cells is confined to a cell subset expressing CD94/NKG2A, but lacking inhibitory killer Ig-like receptors. Eur J Immunol 33:1657Google Scholar
  20. 20.
    Diefenbach A, Jensen ER, Jamieson AM, et al (2001) Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413:165Google Scholar
  21. 21.
    Diefenbach A, Tomasello E, Lucas M, et al (2002) Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nat Immunol 3:1142Google Scholar
  22. 22.
    Dokun AO, Kim S, Smith HR, et al (2001) Specific and nonspecific NK cell activation during virus infection. Nat Immunol 2:951Google Scholar
  23. 23.
    Edwards AD, Diebold SS, Slack EM, et al (2003) Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8 alpha+ DC correlates with unresponsiveness to imidazoquinolines. Eur J Immunol 33:827Google Scholar
  24. 24.
    Ferlazzo G, Morandi B, D’Agostino A, et al (2003) The interaction between NK cells and dendritic cells in bacterial infections results in rapid induction of NK cell activation and in the lysis of uninfected dendritic cells. Eur J Immunol 33:306Google Scholar
  25. 25.
    Ferlazzo G, Munz C (2004) NK cell compartments and their activation by dendritic cells. J Immunol 172:1333Google Scholar
  26. 26.
    Ferlazzo G, Semino C, Melioli G (2001) HLA class I molecule expression is up-regulated during maturation of dendritic cells, protecting them from natural killer cell-mediated lysis. Immunol Lett 76:37Google Scholar
  27. 27.
    Ferlazzo G, Thomas D, Lin SL, et al (2004) The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic. J Immunol 172:1455Google Scholar
  28. 28.
    Ferlazzo G, Tsang ML, Moretta L, et al (2002) Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 195:343Google Scholar
  29. 29.
    Fernandez NC, Lozier A, Flament C, et al (1999) Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat Med 5:405Google Scholar
  30. 30.
    Gallucci S, Lolkema M, Matzinger P (1999) Natural adjuvants: endogenous activators of dendritic cells. Nat Med 5:1249Google Scholar
  31. 31.
    Gao Y, Yang W, Pan M, et al (2003) Gamma delta T cells provide an early source of interferon gamma in tumor immunity. J Exp Med 198:433Google Scholar
  32. 32.
    Garni-Wagner BA, Purohit A, Mathew PA, et al (1993) A novel function-associated molecule related to non-MHC-restricted cytotoxicity mediated by activated natural killer cells and T cells. J Immunol 151:60Google Scholar
  33. 33.
    Geldhof AB, Raes G, Bakkus M, et al (1995) Expression of B7–1 by highly metastatic mouse T lymphomas induces optimal natural killer cell-mediated cytotoxicity. Cancer Res 55:2730Google Scholar
  34. 34.
    Gerosa F, Baldani-Guerra B, Nisii C, et al (2002) Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 195:327Google Scholar
  35. 35.
    Granucci F, Vizzardelli C, Pavelka N, et al (2001) Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nat Immunol 2:882Google Scholar
  36. 36.
    Granucci F, Zanoni I, Pavelka N, et al (2004) A contribution of mouse dendritic cell-derived IL-2 for NK cell activation. J Exp Med 200:287Google Scholar
  37. 37.
    Griffith TS, Chin WA, Jackson GC, et al (1998) Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol 161:2833Google Scholar
  38. 38.
    Haliotis T, Ball JK, Dexter D, et al (1985) Spontaneous and induced primary oncogenesis in natural killer (NK)-cell-deficient beige mutant mice. Int J Cancer 35:505Google Scholar
  39. 39.
    Hashimoto W, Tanaka F, Robbins PD, et al (2003) Natural killer, but not natural killer T, cells play a necessary role in the promotion of an innate antitumor response induced by IL-18. Int J Cancer 103:508Google Scholar
  40. 40.
    Hayakawa Y, Kelly JM, Westwood JA, et al (2002) Cutting edge: tumor rejection mediated by NKG2D receptor-ligand interaction is dependent upon perforin. J Immunol 169:5377Google Scholar
  41. 41.
    Hayakawa Y, Screpanti V, Yagita H, et al (2004) NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy. J Immunol 172:123Google Scholar
  42. 42.
    Hayakawa Y, Takeda K, Yagita H, et al (2002) IFN-gamma-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha-galactosylceramide. Blood 100:1728Google Scholar
  43. 43.
    Houchins JP, Yabe T, McSherry C, et al (1991) DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells. J Exp Med 173:1017Google Scholar
  44. 44.
    Ikeda H, Old LJ, Schreiber RD (2002) The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 13:95Google Scholar
  45. 45.
    Irmler M, Thome M, Hahne M, et al (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388:190Google Scholar
  46. 46.
    Kadowaki N, Ho S, Antonenko S, et al (2001) Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 194:863Google Scholar
  47. 47.
    Karre K, Ljunggren HG, Piontek G, et al (1986) Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319:675Google Scholar
  48. 48.
    Kasaian MT, Whitters MJ, Carter LL, et al (2002) IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity 16:559Google Scholar
  49. 49.
    Kelly JM, Darcy PK, Markby JL, et al (2002) Induction of tumor-specific T cell memory by NK cell-mediated tumor rejection. Nat Immunol 3:83Google Scholar
  50. 50.
    Kelly JM, Takeda K, Darcy PK, et al (2002) A role for IFN-gamma in primary and secondary immunity generated by NK cell-sensitive tumor-expressing CD80 in vivo. J Immunol 168:4472Google Scholar
  51. 51.
    Kennedy MK, Glaccum M, Brown SN, et al (2000) Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med 191:771Google Scholar
  52. 52.
    Kiessling R, Petranyi G, Klein G, et al (1975) Genetic variation of in vitro cytolytic activity and in vivo rejection potential of non-immunized semi-syngeneic mice against a mouse lymphoma line. Int J Cancer 15:933Google Scholar
  53. 53.
    Kim S, Iizuka K, Kang HS, et al (2002) In vivo developmental stages in murine natural killer cell maturation. Nat Immunol 3:523Google Scholar
  54. 54.
    Lanier LL (1998) NK cell receptors. Annu Rev Immunol 16:359Google Scholar
  55. 55.
    Lanier LL, Le AM, Civin CI, et al (1986) The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. J Immunol 136:4480Google Scholar
  56. 56.
    Lian RH, Kumar V (2002) Murine natural killer cell progenitors and their requirements for development. Semin Immunol 14:453Google Scholar
  57. 57.
    Liao NS, Bix M, Zijlstra M, et al (1991) MHC class I deficiency: susceptibility to natural killer (NK) cells and impaired NK activity. Science 253:199Google Scholar
  58. 58.
    Ljunggren HG, Karre K (1985) Host resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanism. J Exp Med 162:1745Google Scholar
  59. 59.
    Loza MJ, Perussia B (2001) Final steps of natural killer cell maturation: a model for type 1-type 2 differentiation? Nat Immunol 2:917Google Scholar
  60. 59a.
    Martin-Fontecha A, Thomsen LL, Brett S et al. (2004) Induced recruitment of NK cells to lymph nodes provides IFN-γ for Th1 priming. Nat Immunol 5:1260Google Scholar
  61. 60.
    McQueen KL, Parham P (2002) Variable receptors controlling activation and inhibition of NK cells. Curr Opin Immunol 14:615Google Scholar
  62. 61.
    Medzhitov R, Janeway CA Jr (1998) Innate immune recognition and control of adaptive immune responses. Semin Immunol 10:351Google Scholar
  63. 62.
    Mellman I, Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255Google Scholar
  64. 63.
    Mocikat R, Braumuller H, Gumy A, et al (2003) Natural killer cells activated by MHC class I(low) targets prime dendritic cells to induce protective CD8 T cell responses. Immunity 19:561Google Scholar
  65. 64.
    Moroz A, Eppolito C, Li Q, et al (2004) IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: comparative evaluation of IL-2, IL-15, and IL-21. J Immunol 173:900Google Scholar
  66. 65.
    Moser M (2003) Dendritic cells in immunity and tolerance-do they display opposite functions? Immunity 19:5Google Scholar
  67. 66.
    O’Hanlon LH (2004) Natural born killers: NK cells drafted into the cancer fight. J Natl Cancer Inst 96:651Google Scholar
  68. 67.
    Ogasawara K, Yoshinaga SK, Lanier LL (2002) Inducible costimulator costimulates cytotoxic activity and IFN-gamma production in activated murine NK cells. J Immunol 169: 3676Google Scholar
  69. 68.
    Pawelec G, Da Silva P, Max H, et al (1995) Relative roles of natural killer- and T cell-mediated anti-leukemia effects in chronic myelogenous leukemia patients treated with interferon-alpha. Leuk Lymphoma 18:471Google Scholar
  70. 69.
    Peritt D, Robertson S, Gri G, et al (1998) Differentiation of human NK cells into NK1 and NK2 subsets. J Immunol 161:5821Google Scholar
  71. 70.
    Piccioli D, Sbrana S, Melandri E, et al (2002) Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med 195:335Google Scholar
  72. 71.
    Reis e Sousa C, Diebold SD, Edwards AD, et al (2003) Regulation of dendritic cell function by microbial stimuli. Pathol Biol (Paris) 51:67Google Scholar
  73. 72.
    Robertson MJ (2002) Role of chemokines in the biology of natural killer cells. J Leukoc Biol 71:173Google Scholar
  74. 73.
    Rosenberg SA (2000) Interleukin-2 and the development of immunotherapy for the treatment of patients with cancer. Cancer J Sci Am 6 Suppl 1: S2Google Scholar
  75. 74.
    Roth C, Carlyle JR, Takizawa H, et al (2000) Clonal acquisition of inhibitory Ly49 receptors on developing NK cells is successively restricted and regulated by stromal class I MHC. Immunity 13:143Google Scholar
  76. 75.
    Ruggeri L, Capanni M, Urbani E, et al (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295: 2097Google Scholar
  77. 76.
    Sauter B, Albert ML, Francisco L, et al (2000) Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J Exp Med 191:423Google Scholar
  78. 77.
    Screpanti V, Wallin RP, Ljunggren HG, et al (2001) A central role for death receptor-mediated apoptosis in the rejection of tumors by NK cells. J Immunol 167:2068Google Scholar
  79. 78.
    Seya T, Akazawa T, Uehori J, et al (2003) Role of toll-like receptors and their adaptors in adjuvant immunotherapy for cancer. Anticancer Res 23:4369Google Scholar
  80. 79.
    Shortman K, Liu YJ (2002) Mouse and human dendritic cell subtypes. Nat Rev Immunol 2:151Google Scholar
  81. 80.
    Silla LM, Whiteside TL, Ball ED (1995) The role of natural killer cells in the treatment of chronic myeloid leukemia. J Hematother 4:269Google Scholar
  82. 81.
    Sivakumar PV, Foster DC, Clegg CH (2004) Interleukin-21 is a T-helper cytokine that regulates humoral immunity and cell-mediated anti-tumour responses. Immunology 112:177Google Scholar
  83. 82.
    Sivori S, Falco M, Della Chiesa M, et al (2004) CpG and double-stranded RNA trigger human NK cells by Toll-like receptors: induction of cytokine release and cytotoxicity against tumors and dendritic cells. Proc Natl Acad Sci USA 101:10116Google Scholar
  84. 83.
    Smyth MJ, Cretney E, Takeda K, et al (2001) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. J Exp Med 193:661Google Scholar
  85. 84.
    Smyth MJ, Crowe NY, Godfrey DI (2001) NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int Immunol 13:459Google Scholar
  86. 85.
    Smyth MJ, Hayakawa Y, Takeda K, et al (2002) New aspects of natural-killer-cell surveillance and therapy of cancer. Nat Rev Cancer 2:850Google Scholar
  87. 86.
    Smyth MJ, Street SE, Trapani JA (2003) Cutting edge: granzymes A and B are not essential for perforin-mediated tumor rejection. J Immunol 171:515Google Scholar
  88. 87.
    Smyth MJ, Takeda K, Hayakawa Y, et al (2003) Nature’s TRAIL—on a path to cancer immunotherapy. Immunity 18:1Google Scholar
  89. 88.
    Smyth MJ, Taniguchi M, Street SE (2000) The anti-tumor activity of IL-12: mechanisms of innate immunity that are model and dose dependent. J Immunol 165:2665Google Scholar
  90. 89.
    Smyth MJ, Thia KY, Cretney E, et al (1999) Perforin is a major contributor to NK cell control of tumor metastasis. J Immunol 162:6658Google Scholar
  91. 90.
    Smyth MJ, Thia KY, Street SE, et al (2000) Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med 191:661Google Scholar
  92. 91.
    Smyth MJ, Thia KY, Street SE, et al (2000) Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med 192:755Google Scholar
  93. 92.
    Smyth MJ, Trapani JA (1995) Granzymes: exogenous proteinases that induce target cell apoptosis. Immunol Today 16:202Google Scholar
  94. 93.
    Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al (1999) Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286:1957Google Scholar
  95. 94.
    Street SE, Cretney E, Smyth MJ (2001) Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. Blood 97:192Google Scholar
  96. 95.
    Street SE, Hayakawa Y, Zhan Y, et al (2004) Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and γδ T cells. J Exp Med 199:879Google Scholar
  97. 96.
    Takeda K, Hayakawa Y, Smyth MJ, et al (2001) Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 7:94Google Scholar
  98. 97.
    Takeda K, Smyth MJ, Cretney E, et al (2002) Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med 195:161Google Scholar
  99. 98.
    Takei F, McQueen KL, Maeda M, et al (2001) Ly49 and CD94/NKG2: developmentally regulated expression and evolution. Immunol Rev 181:90Google Scholar
  100. 99.
    Trapani JA, Smyth MJ (2002) Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2:735Google Scholar
  101. 100.
    Trinchieri G (1998) Immunobiology of interleukin-12. Immunol Res 17:269Google Scholar
  102. 101.
    Van den Broek MF, Kagi D, Zinkernagel RM, et al (1995) Perforin dependence of natural killer cell-mediated tumor control in vivo. Eur J Immunol 25:3514Google Scholar
  103. 102.
    Waldmann TA, Tagaya Y (1999) The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. Annu Rev Immunol 17:19Google Scholar
  104. 103.
    Whiteside TL, Herberman RB (1995) The role of natural killer cells in immune surveillance of cancer. Curr Opin Immunol 7:704Google Scholar
  105. 104.
    Whiteside TL, Vujanovic NL and Herberman RB (1998) Natural killer cells and tumor therapy. Curr Top Microbiol Immunol 230:221Google Scholar
  106. 105.
    Williams NS, Moore TA, Schatzle JD, et al (1997) Generation of lytic natural killer 1.1+, Ly-49- cells from multipotential murine bone marrow progenitors in a stroma-free culture: definition of cytokine requirements and developmental intermediates. J Exp Med 186:1609Google Scholar
  107. 106.
    Wilson JL, Heffler LC, Charo J, et al (1999) Targeting of human dendritic cells by autologous NK cells. J Immunol 163:6365Google Scholar
  108. 107.
    Wilson MJ, Torkar M, Haude A, et al (2000) Plasticity in the organization and sequences of human KIR/ILT gene families. Proc Natl Acad Sci USA 97:4778Google Scholar
  109. 108.
    Wooldridge JE, Weiner GJ (2003) CpG DNA and cancer immunotherapy: orchestrating the antitumor immune response. Curr Opin Oncol 15:440Google Scholar
  110. 109.
    Wu J, Lanier LL (2003) Natural killer cells and cancer. Adv Cancer Res 90:127Google Scholar
  111. 110.
    Yasumura S, Lin WC, Hirabayashi H, et al (1994) Immunotherapy of liver metastases of human gastric carcinoma with interleukin 2-activated natural killer cells. Cancer Res 54:3808Google Scholar
  112. 111.
    Yokoyama WM, Daniels BF, Seaman WE, et al (1995) A family of murine NK cell receptors specific for target cell MHC class I molecules. Semin Immunol 7:89Google Scholar
  113. 112.
    Yokoyama WM, Plougastel BF (2003) Immune functions encoded by the natural killer gene complex. Nat Rev Immunol 3:304Google Scholar
  114. 113.
    Yuan D, Koh CY, Wilder JA (1994) Interactions between B lymphocytes and NK cells. FASEB J, 8:1012Google Scholar
  115. 114.
    Zitvogel L (2002) Dendritic and natural killer cells cooperate in the control/switch of innate immunity. J Exp Med 195:F9Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  1. 1.Cancer Immunology Program, Sir Donald and Lady Trescowthick LaboratoriesPeter MacCallum Cancer CentreEast MelbourneAustralia

Personalised recommendations