Natural killer cells: role in local tumor growth and metastasis

: Historically, the name of natural killer (NK) cells came from their natural ability to kill tumor cells in vitro. From the 1970s to date, accumulating data highlighted the importance of NK cells in host immune response against cancer and in therapy-induced antitumor response. The recognition and the lysis of tumor cells by NK cells are regulated by a complex balance of inhibitory and activating signals. This review summarizes NK cell mechanisms to kill cancer cells, their role in host immune responses against tumor growth or metastasis, and their implications in antitumor immunotherapies via cytokines, antibodies, or in combination with other therapies. The regulatory role of NK cells in autoimmunity is also discussed.

[1]  Michael Hagemann-Jensen,et al.  2-Deoxy d-Glucose Prevents Cell Surface Expression of NKG2D Ligands through Inhibition of N-Linked Glycosylation , 2012, The Journal of Immunology.

[2]  Juan Ma,et al.  Establishment, Characterization, and Successful Adaptive Therapy against Human Tumors of NKG Cell, a New Human NK Cell Line , 2011, Cell transplantation.

[3]  S. Kawakami,et al.  The involvement of NK cell activation following intranasal administration of CpG DNA lipoplex in the prevention of pulmonary metastasis and peritoneal dissemination in mice , 2011, Clinical & Experimental Metastasis.

[4]  P. Delvenne,et al.  Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion , 2011, European journal of immunology.

[5]  Ami A. Shah,et al.  Cancer and systemic sclerosis: novel insights into pathogenesis and clinical implications , 2011, Current opinion in rheumatology.

[6]  H. Hauser,et al.  IRF-1 expression is essential for natural killer cells to suppress metastasis. , 2011, Cancer research.

[7]  P. Darcy,et al.  Autoimmunity associated with immunotherapy of cancer. , 2011, Blood.

[8]  S. Khakoo,et al.  KIR/HLA Interactions and Pathogen Immunity , 2011, Journal of biomedicine & biotechnology.

[9]  F. Shi,et al.  Natural killer cells as indispensable players and therapeutic targets in autoimmunity , 2011, Autoimmunity.

[10]  E. Alici.  IPH-2101, a fully human anti-NK-cell inhibitory receptor mAb for the potential treatment of hematological cancers. , 2010, Current opinion in molecular therapeutics.

[11]  J. García-Foncillas,et al.  Progress in metastatic colorectal cancer: growing role of cetuximab to optimize clinical outcome , 2010, Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico.

[12]  J. Foidart,et al.  Local Applications of GM‐CSF Induce the Recruitment of Immune Cells in Cervical Low‐Grade Squamous Intraepithelial Lesions , 2010, American journal of reproductive immunology.

[13]  H. Goossens,et al.  Induction of complete and molecular remissions in acute myeloid leukemia by Wilms’ tumor 1 antigen-targeted dendritic cell vaccination , 2010, Proceedings of the National Academy of Sciences.

[14]  L. Lanier,et al.  Effect of NKG2D ligand expression on host immune responses , 2010, Immunological reviews.

[15]  F. Navid,et al.  Anti-GD2 antibody therapy for GD2-expressing tumors. , 2010, Current cancer drug targets.

[16]  L. Zitvogel,et al.  Dendritic cell-derived exosomes for cancer immunotherapy: what's next? , 2010, Cancer research.

[17]  M. Grever,et al.  A phase I trial of paclitaxel and trastuzumab in combination with interleukin-12 in patients with HER2/neu-expressing malignancies , 2009, Molecular Cancer Therapeutics.

[18]  S. Riddell,et al.  Safety and immunologic effects of IL-15 administration in nonhuman primates. , 2009, Blood.

[19]  Eric Vivier,et al.  The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans , 2009, The Journal of experimental medicine.

[20]  J. Lünemann,et al.  Regulatory NK-Cell Functions in Inflammation and Autoimmunity , 2009, Molecular medicine.

[21]  R. Hynes,et al.  Natural killer cells require selectins for suppression of subcutaneous tumors. , 2009, Cancer research.

[22]  K. Eguchi,et al.  A significantly impaired natural killer cell activity due to a low activity on a per-cell basis in rheumatoid arthritis , 2009, Modern rheumatology.

[23]  B. Hancock,et al.  Ten years of rituximab in NHL , 2009, Expert opinion on drug safety.

[24]  A. Cerwenka.  New twist on the regulation of NKG2D ligand expression , 2009, The Journal of experimental medicine.

[25]  H. Achdout,et al.  Enhanced In Vivo Growth of Lymphoma Tumors in the Absence of the NK-Activating Receptor NKp46/NCR11 , 2009, The Journal of Immunology.

[26]  A. Porgador,et al.  Natural cytotoxicity receptors NKp30, NKp44 and NKp46 bind to different heparan sulfate/heparin sequences. , 2009, Journal of proteome research.

[27]  Eric Vivier,et al.  Functions of natural killer cells , 2008, Nature Immunology.

[28]  P. Delvenne,et al.  Innate lymphocyte and dendritic cell cross‐talk: a key factor in the regulation of the immune response , 2008, Clinical and experimental immunology.

[29]  T. Beddoe,et al.  CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence , 2008, The Journal of experimental medicine.

[30]  Michael Hallek,et al.  Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. , 2007, Immunity.

[31]  T. Ley,et al.  Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. , 2007, Immunity.

[32]  M. Smyth,et al.  NK cell-based cancer immunotherapy. , 2007, Drug news & perspectives.

[33]  J. Ravetch,et al.  Antibodies, Fc receptors and cancer. , 2007, Current opinion in immunology.

[34]  Eric Vivier,et al.  Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46 , 2007, Proceedings of the National Academy of Sciences.

[35]  P. Delvenne,et al.  Dendritic Cells: More Than Just Adaptive Immunity Inducers? , 2007 .

[36]  Eric O Long,et al.  Activation, coactivation, and costimulation of resting human natural killer cells , 2006, Immunological reviews.

[37]  J. Coligan,et al.  CD94/NKG2A Inhibits NK Cell Activation by Disrupting the Actin Network at the Immunological Synapse1 , 2006, The Journal of Immunology.

[38]  M. Caligiuri,et al.  Tumor growth impedes natural-killer-cell maturation in the bone marrow. , 2006, Blood.

[39]  T. Waldmann,et al.  Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[40]  M. Smyth,et al.  CD27 Dissects Mature NK Cells into Two Subsets with Distinct Responsiveness and Migratory Capacity1 , 2006, The Journal of Immunology.

[41]  D. F. Barber,et al.  Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells , 2005, The Journal of experimental medicine.

[42]  M. Smyth,et al.  NKG2D function protects the host from tumor initiation , 2005, The Journal of experimental medicine.

[43]  R. Nussenblatt,et al.  Cutting edge: in vivo blockade of human IL-2 receptor induces expansion of CD56bright regulatory NK cells in patients with active uveitis , 2005, The Journal of Immunology.

[44]  Eric J. Brown,et al.  The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor , 2005, Nature.

[45]  L. Lanier.  Missing Self, NK Cells, and The White Album , 2005, The Journal of Immunology.

[46]  M. Korc,et al.  Membrane-Associated Heparan Sulfate Proteoglycans Are Involved in the Recognition of Cellular Targets by NKp30 and NKp461 , 2004, The Journal of Immunology.

[47]  L. Lanier,et al.  A Structural Basis for the Association of DAP12 with Mouse, but Not Human, NKG2D1 , 2004, The Journal of Immunology.

[48]  T. Krieg,et al.  Association of killer cell immunoglobulin-like receptors with scleroderma. , 2004, Arthritis and rheumatism.

[49]  T. Sasazuki,et al.  Genetic polymorphisms of killer cell immunoglobulin-like receptors are associated with susceptibility to psoriasis vulgaris. , 2004, The Journal of investigative dermatology.

[50]  E. Hewitt.  The MHC class I antigen presentation pathway: strategies for viral immune evasion , 2003, Immunology.

[51]  S. Ohno,et al.  Diminution of experimental autoimmune uveoretinitis (EAU) in mice depleted of NK cells , 2002, Journal of leukocyte biology.

[52]  Michael J. Wilson,et al.  Cutting Edge: Susceptibility to Psoriatic Arthritis: Influence of Activating Killer Ig-Like Receptor Genes in the Absence of Specific HLA-C Alleles1 , 2002, The Journal of Immunology.

[53]  D. Olive,et al.  Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia. , 2002, Blood.

[54]  C. Sutherland,et al.  UL16-Binding Proteins, Novel MHC Class I-Related Proteins, Bind to NKG2D and Activate Multiple Signaling Pathways in Primary NK Cells , 2002, The Journal of Immunology.

[55]  A. Diefenbach,et al.  Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity , 2001, Nature.

[56]  G. Konjević,et al.  Impaired Perforin-Dependent NK Cell Cytotoxicity and Proliferative Activity of Peripheral Blood T Cells is Associated with Metastatic Melanoma , 2001, Tumori.

[57]  J. Hank,et al.  Antibody-directed, effector cell-mediated tumor destruction. , 2001, Hematology/oncology clinics of North America.

[58]  W. Murphy,et al.  Augmentation of antitumor effects by NK cell inhibitory receptor blockade in vitro and in vivo. , 2001, Blood.

[59]  R. Biassoni,et al.  Role of NKG2D in tumor cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumors of nonepithelial origin , 2001, European journal of immunology.

[60]  M. Smyth,et al.  Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (Trail) Contributes to Interferon γ–Dependent Natural Killer Cell Protection from Tumor Metastasis , 2001, The Journal of experimental medicine.

[61]  F. Shi,et al.  Innate immunity and autoimmunity: from self-protection to self-destruction. , 2001, Trends in immunology.

[62]  K. Nakachi,et al.  Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population , 2000, The Lancet.

[63]  J. Trapani,et al.  Perforin-Mediated Cytotoxicity Is Critical for Surveillance of Spontaneous Lymphoma , 2000, The Journal of experimental medicine.

[64]  F. Shi,et al.  Natural killer cells determine the outcome of B cell–mediated autoimmunity , 2000, Nature Immunology.

[65]  J. Renauld,et al.  Cytokine Production and Killer Activity of NK/T-NK Cells Derived with IL-2, IL-15, or the Combination of IL-12 and IL-181 , 2000, The Journal of Immunology.

[66]  J. Yen,et al.  Killer Cell Activating Receptors Function as Costimulatory Molecules on CD4+CD28null T Cells Clonally Expanded in Rheumatoid Arthritis1 , 2000, The Journal of Immunology.

[67]  I. Weissman,et al.  In vivo natural killer cell activities revealed by natural killer cell-deficient mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[68]  R. Biassoni,et al.  Identification and Molecular Characterization of Nkp30, a Novel Triggering Receptor Involved in Natural Cytotoxicity Mediated by Human Natural Killer Cells , 1999, The Journal of experimental medicine.

[69]  A Steinle,et al.  Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. , 1999, Science.

[70]  E. Wisse,et al.  Involvement of LFA-1 in hepatic NK cell (pit cell)-mediated cytolysis and apoptosis of colon carcinoma cells. , 1999, Journal of hepatology.

[71]  R. Fisher,et al.  High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[72]  C. Sautès-Fridman,et al.  Regulation of production of soluble Fc gamma receptors type III in normal and pathological conditions. , 1999, Immunology letters.

[73]  R. Biassoni,et al.  NKp46 is the major triggering receptor involved in the natural cytotoxicity of fresh or cultured human NK cells. Correlation between surface density of NKp46 and natural cytotoxicity against autologous, allogeneic or xenogeneic target cells , 1999, European journal of immunology.

[74]  R. Biassoni,et al.  NKp44, A Triggering Receptor Involved in Tumor Cell Lysis by Activated Human Natural Killer Cells, Is a Novel Member of the Immunoglobulin Superfamily , 1999, The Journal of experimental medicine.

[75]  E. Alnemri,et al.  Natural Killer (NK) Cell–mediated Cytotoxicity: Differential Use of  TRAIL and Fas Ligand by Immature and Mature Primary Human NK Cells , 1998, The Journal of experimental medicine.

[76]  P. Kalinski,et al.  High-level IL-12 production by human dendritic cells requires two signals. , 1998, International immunology.

[77]  R. Biassoni,et al.  Molecular Cloning of NKp46: A Novel Member of the Immunoglobulin Superfamily Involved in Triggering of Natural Cytotoxicity , 1998, The Journal of experimental medicine.

[78]  L. Moretta,et al.  NKp44, a Novel Triggering Surface Molecule Specifically Expressed by Activated Natural Killer Cells, Is Involved in Non–Major Histocompatibility Complex–restricted Tumor Cell Lysis , 1998, The Journal of experimental medicine.

[79]  W. Yokoyama.  Natural killer cell receptors. , 1998, Current opinion in immunology.

[80]  K. Matsumoto,et al.  Murine Nkg2d and Cd94 are clustered within the natural killer complex and are expressed independently in natural killer cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[81]  M. Llano,et al.  Specific engagement of the CD94/NKG2‐A killer inhibitory receptor by the HLA‐E class Ib molecule induces SHP‐1 phosphatase recruitment to tyrosine‐phosphorylated NKG2‐A: evidence for receptor function in heterologous transfectants , 1998, European journal of immunology.

[82]  Jun Wu,et al.  Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells , 1998, Nature.

[83]  Eric Vivier,et al.  Inhibition of antigen‐induced T cell response and antibody‐induced NK cell cytotoxicity by NKG2A: association of NKG2A with SHP‐1 and SHP‐2 protein‐tyrosine phosphatases , 1998, European journal of immunology.

[84]  L. Moretta,et al.  p46, a Novel Natural Killer Cell–specific Surface Molecule That Mediates Cell Activation , 1997, The Journal of experimental medicine.

[85]  É. Vivier,et al.  Human killer cell activatory receptors for MHC class I molecules are included in a multimeric complex expressed by natural killer cells. , 1997, Journal of immunology.

[86]  L. Lanier.  Natural killer cells: from no receptors to too many. , 1997, Immunity.

[87]  M. Carretero,et al.  The CD94 and NKG2‐A C‐type lectins covalently assemble to form a natural killer cell inhibitory receptor for HLA class I molecules , 1997, European journal of immunology.

[88]  S. Bahram,et al.  Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[89]  Eric O Long,et al.  Killer cell inhibitory receptors specific for HLA-C and HLA-B identified by direct binding and by functional transfer. , 1995, Immunity.

[90]  H. Kleinman,et al.  Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo , 1995, The Journal of experimental medicine.

[91]  G. Trinchieri.  Natural killer cells wear different hats: effector cells of innate resistance and regulatory cells of adaptive immunity and of hematopoiesis. , 1995, Seminars in immunology.

[92]  Hans Hengartner,et al.  Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice , 1994, Nature.

[93]  J. Gong,et al.  Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. , 1994, Leukemia.

[94]  D. Isenberg,et al.  Lymphocyte Subsets in a Large Cohort of Patients with Systemic Lupus Erythematosus , 1993, Lupus.

[95]  S. Powis,et al.  Tumorigenicity conferred to lymphoma mutant by major histocompatibility complex-encoded transporter gene , 1993, The Journal of experimental medicine.

[96]  F. Bach,et al.  DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells , 1991, The Journal of experimental medicine.

[97]  J. Ritz,et al.  Biology and clinical relevance of human natural killer cells. , 1990, Blood.

[98]  H. Ljunggren,et al.  Transfection of beta 2-microglobulin restores IFN-mediated protection from natural killer cell lysis in YAC-1 lymphoma variants. , 1990, Journal of immunology.

[99]  G. Trinchieri,et al.  Biology of Natural Killer Cells , 1989, Advances in Immunology.

[100]  L. Lanier,et al.  Comparative studies of human FcRIII-positive and negative natural killer cells. , 1989, Journal of immunology.

[101]  E. Shevach,et al.  A murine T lymphocyte antigen belongs to a supergene family of type II integral membrane proteins. , 1989, Journal of immunology.

[102]  C. Biron,et al.  Murine natural killer cells stimulated in vivo do not express the T cell receptor alpha, beta, gamma, T3 delta, or T3 epsilon genes. , 1987, Journal of immunology.

[103]  J. Markowitz,et al.  Cancer family syndrome: marker studies. , 1986, Gastroenterology.

[104]  H. Ljunggren,et al.  Selective rejection of H–2-deficient lymphoma variants suggests alternative immune defence strategy , 1986, Nature.

[105]  H. Ljunggren,et al.  Host resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanism , 1985, The Journal of experimental medicine.

[106]  E. Gardner,et al.  Deficient immune function of peripheral blood mononuclear cells from patients with Gardner syndrome. , 1985, Clinical and experimental immunology.

[107]  C. Riccardi,et al.  In vivo natural reactivity of mice against tumor cells , 1980, International journal of cancer.

[108]  G. Trinchieri,et al.  Human natural killer cells. , 1979, Transplantation proceedings.

[109]  G. Cannon,et al.  Specificity of natural cytotoxic reactivity of normal human lymphocytes against a myeloid leukemia cell line. , 1977, Journal of the National Cancer Institute.

[110]  R. Kiessling,et al.  „Natural”︁ killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype , 1975, European journal of immunology.

[111]  L. Lanier,et al.  Inhibitory Ly49 receptors on mouse natural killer cells. , 2011, Current topics in microbiology and immunology.

[112]  M. Smyth,et al.  Alloreactive natural killer cells in hematopoietic stem cell transplantation. , 2011, Leukemia research.

[113]  G. Keating,et al.  Trastuzumab: A review of its use as adjuvant treatment in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. , 2010, Drugs.

[114]  J. D. Di Santo.  Natural killer cell developmental pathways: a question of balance. , 2006, Annual review of immunology.

[115]  L. Lanier,et al.  Viral modulation of NK cell immunity , 2005, Nature Reviews Microbiology.

[116]  J. Bluestone,et al.  Impairment of NK cell function by NKG2D modulation in NOD mice. , 2003, Immunity.

[117]  Lewis L Lanier,et al.  Natural killer cells and cancer. , 2003, Advances in cancer research.

[118]  U. Koszinowski,et al.  Natural killer cells activated by MHC class I(low) targets prime dendritic cells to induce protective CD8 T cell responses. , 2003, Immunity.

[119]  M. Smyth,et al.  Induction of tumor-specific T cell memory by NK cell–mediated tumor rejection , 2002, Nature Immunology.

[120]  M. Smyth,et al.  Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. , 2001, Blood.

[121]  F. Garrido,et al.  MHC antigens and tumor escape from immune surveillance. , 2001, Advances in cancer research.

[122]  M. Smyth,et al.  Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells , 2001, Nature Medicine.

[123]  M. Smyth,et al.  NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. , 2001, International immunology.

[124]  T. Ghayur,et al.  Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. , 2001, Blood.

[125]  R. Vance,et al.  Regulation of the natural killer cell receptor repertoire. , 2001, Annual review of immunology.

[126]  J. Gołąb,et al.  Potentiatied anti-tumor effectiveness of combined therapy with interleukin-12 and mitoxantrone of L1210 leukemia in vivo. , 2000, Oncology reports.

[127]  R. Biassoni,et al.  The human natural cytotoxicity receptors (NCR) that induce HLA class I-independent NK cell triggering. , 2000, Human immunology.

[128]  C. Biron,et al.  Natural killer cells in antiviral defense: function and regulation by innate cytokines. , 1999, Annual review of immunology.

[129]  Y. W. Loke,et al.  Human uterine natural killer cells. , 1996, Natural immunity.

[130]  R. Bechhofer,et al.  Prolonged interleukin-2 (IL-2) treatment can augment immune activation without enhancing antitumor activity in renal cell carcinoma. , 1991, Cancer investigation.

[131]  M. Clément,et al.  Involvement of granzyme B and perforin gene expression in the lytic potential of human natural killer cells. , 1990, Nouvelle revue francaise d'hematologie.

[132]  T. Takahashi.  [Erythematosus]. , 1971, Nihon rinsho. Japanese journal of clinical medicine.