Cancer Microenvironment

, Volume 6, Issue 2, pp 135–146 | Cite as

Shaping of NK Cell Responses by the Tumor Microenvironment

  • Ana Stojanovic
  • Margareta P. Correia
  • Adelheid Cerwenka
Original Article


Natural killer (NK) cells belong to the innate immune system and are potent cytolytic and cytokine-producing effector cells in response to tumor targets. NK cell based anti-tumor immunotherapy was so far mainly successful in patients with different types of leukemia. For instance, acute myeloid leukemia (AML) patients displayed a prolonged survival if transplanted with haploidentical stem cells giving rise to NK cells with a mismatch in inhibitory killer immunoglobulin receptors (KIRs) and recipients’ HLA class I. Although promising results have been achieved with hematological tumors, solid tumors are in most cases poorly controlled by NK cells. Therapeutic protocols that aimed at improving NK cell responses in patients with solid malignancies succeeded in increasing NK cell numbers and functional responses of NK cells isolated from the patients’ peripheral blood. However, in the majority of cases tumor progression and overall survival of patients were not significantly improved. There is increasing evidence that tumor-associated NK cells become gradually impaired during tumor progression compared to NK cells from peripheral blood and healthy tissues. Future protocols of NK cell based immunotherapy should integrate three important aspects to improve NK cell anti-tumor activity: facilitating NK cell migration to the tumor site, enhancing their infiltration into the tumor tissue and ensuring subsequent efficient activation in the tumor. This review summarizes the current knowledge of tumor-infiltrating NK cells and the influence of the tumor microenvironment on their phenotype and function.


NK cells Tumor immunology Tumor microenvironment 


  1. 1.
    Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F, Vermorken JB (2010) Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC Immunol 11:19PubMedGoogle Scholar
  2. 2.
    Coca S, Perez-Piqueras J, Martinez D, Colmenarejo A, Saez MA, Vallejo C, Martos JA, Moreno M (1997) The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer 79(12):2320–2328PubMedGoogle Scholar
  3. 3.
    Kerkar SP, Restifo NP (2012) Cellular constituents of immune escape within the tumor microenvironment. Cancer Res 72(13):3125–3130PubMedGoogle Scholar
  4. 4.
    Facciabene A, Motz GT, Coukos G (2012) T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res 72(9):2162–2171PubMedGoogle Scholar
  5. 5.
    Nagaraj S, Gabrilovich DI (2008) Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res 68(8):2561–2563PubMedGoogle Scholar
  6. 6.
    Bryceson YT, Long EO (2008) Line of attack: NK cell specificity and integration of signals. Curr Opin Immunol 20(3):344–352PubMedGoogle Scholar
  7. 7.
    Moretta L, Locatelli F, Pende D, Mingari MC, Moretta A (2010) Natural killer alloeffector responses in haploidentical hemopoietic stem cell transplantation to treat high-risk leukemias. Tissue Antigens 75(2):103–109PubMedGoogle Scholar
  8. 8.
    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(5562):2097–2100PubMedGoogle Scholar
  9. 9.
    Benson DM Jr, Hofmeister CC, Padmanabhan S, Suvannasankha A, Jagganath S, Abonour R, Bakan C, Andre P, Efebera Y, Tiollier J, Caligiuri MA, Farag SS (2012) A phase I trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma. Blood. doi: 10.1182/blood-2012-06-438028, Published online Oct 1
  10. 10.
    Vey N, Bourhis JH, Boissel N, Bordessoule D, Prebet T, Charbonnier A, Etienne A, Andre P, Romagne F, Benson D, Dombret H, Olive D (2012) A phase I trial of the anti-inhibitory KIR monoclonal antibody IPH2101 for acute myeloid leukemia (AML) in complete remission. Blood. doi: 10.1182/blood-2012-06-437558, Published online Sep 21
  11. 11.
    Venstrom JM, Pittari G, Gooley TA, Chewning JH, Spellman S, Haagenson M, Gallagher MM, Malkki M, Petersdorf E, Dupont B, Hsu KC (2012) HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1. N Engl J Med 367(9):805–816PubMedGoogle Scholar
  12. 12.
    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(5):486–494PubMedGoogle Scholar
  13. 13.
    Andrews DM, Maraskovsky E, Smyth MJ (2008) Cancer vaccines for established cancer: how to make them better? Immunol Rev 222:242–255PubMedGoogle Scholar
  14. 14.
    Alderson KL, Sondel PM (2011) Clinical cancer therapy by NK cells via antibody-dependent cell-mediated cytotoxicity. J Biomed Biotechnol 2011:379123PubMedGoogle Scholar
  15. 15.
    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(2):117–121PubMedGoogle Scholar
  16. 16.
    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(2):112–117PubMedGoogle Scholar
  17. 17.
    Bryceson YT, March ME, Ljunggren HG, Long EO (2006) Activation, coactivation, and costimulation of resting human natural killer cells. Immunol Rev 214:73–91PubMedGoogle Scholar
  18. 18.
    Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A (2007) Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 26(4):503–517PubMedGoogle Scholar
  19. 19.
    Bihl F, Pecheur J, Breart B, Poupon G, Cazareth J, Julia V, Glaichenhaus N, Braud VM (2010) Primed antigen-specific CD4+ T cells are required for NK cell activation in vivo upon Leishmania major infection. J Immunol 185(4):2174–2181PubMedGoogle Scholar
  20. 20.
    Sporri R, Joller N, Hilbi H, Oxenius A (2008) A novel role for neutrophils as critical activators of NK cells. J Immunol 181(10):7121–7130PubMedGoogle Scholar
  21. 21.
    Jaeger BN, Donadieu J, Cognet C, Bernat C, Ordonez-Rueda D, Barlogis V, Mahlaoui N, Fenis A, Narni-Mancinelli E, Beaupain B, Bellanne-Chantelot C, Bajenoff M, Malissen B, Malissen M, Vivier E, Ugolini S (2012) Neutrophil depletion impairs natural killer cell maturation, function, and homeostasis. J Exp Med 209(3):565–580PubMedGoogle Scholar
  22. 22.
    Zwirner NW, Domaica CI (2010) Cytokine regulation of natural killer cell effector functions. Biofactors 36(4):274–288PubMedGoogle Scholar
  23. 23.
    Nausch N, Cerwenka A (2008) NKG2D ligands in tumor immunity. Oncogene 27(45):5944–5958PubMedGoogle Scholar
  24. 24.
    Raulet DH (2003) Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 3(10):781–790PubMedGoogle Scholar
  25. 25.
    Raulet DH, Guerra N (2009) Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat Rev Immunol 9(8):568–580PubMedGoogle Scholar
  26. 26.
    Soriani A, Zingoni A, Cerboni C, Iannitto ML, Ricciardi MR, Di Gialleonardo V, Cippitelli M, Fionda C, Petrucci MT, Guarini A, Foa R, Santoni A (2009) ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood 113(15):3503–3511PubMedGoogle Scholar
  27. 27.
    Chan CJ, Andrews DM, McLaughlin NM, Yagita H, Gilfillan S, Colonna M, Smyth MJ (2010) DNAM-1/CD155 interactions promote cytokine and NK cell-mediated suppression of poorly immunogenic melanoma metastases. J Immunol 184(2):902–911PubMedGoogle Scholar
  28. 28.
    Smyth MJ, Swann J, Kelly JM, Cretney E, Yokoyama WM, Diefenbach A, Sayers TJ, Hayakawa Y (2004) NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer. J Exp Med 200(10):1325–1335PubMedGoogle Scholar
  29. 29.
    Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, Knoblaugh S, Cado D, Greenberg NM, Raulet DH (2008) NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 28(4):571–580PubMedGoogle Scholar
  30. 30.
    Pogge von Strandmann E, Simhadri VR, von Tresckow B, Sasse S, Reiners KS, Hansen HP, Rothe A, Boll B, Simhadri VL, Borchmann P, McKinnon PJ, Hallek M, Engert A (2007) Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. Immunity 27(6):965–974PubMedGoogle Scholar
  31. 31.
    Simhadri VR, Reiners KS, Hansen HP, Topolar D, Simhadri VL, Nohroudi K, Kufer TA, Engert A, Pogge von Strandmann E (2008) Dendritic cells release HLA-B-associated transcript-3 positive exosomes to regulate natural killer function. PLoS One 3(10):e3377PubMedGoogle Scholar
  32. 32.
    Brandt CS, Baratin M, Yi EC, Kennedy J, Gao Z, Fox B, Haldeman B, Ostrander CD, Kaifu T, Chabannon C, Moretta A, West R, Xu W, Vivier E, Levin SD (2009) The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J Exp Med 206(7):1495–1503PubMedGoogle Scholar
  33. 33.
    Delahaye NF, Rusakiewicz S, Martins I, Menard C, Roux S, Lyonnet L, Paul P, Sarabi M, Chaput N, Semeraro M, Minard-Colin V, Poirier-Colame V, Chaba K, Flament C, Baud V, Authier H, Kerdine-Romer S, Pallardy M, Cremer I, Peaudecerf L, Rocha B, Valteau-Couanet D, Gutierrez JC, Nunes JA, Commo F, Bonvalot S, Ibrahim N, Terrier P, Opolon P, Bottino C, Moretta A, Tavernier J, Rihet P, Coindre JM, Blay JY, Isambert N, Emile JF, Vivier E, Lecesne A, Kroemer G, Zitvogel L (2011) Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat Med 17(6):700–707PubMedGoogle Scholar
  34. 34.
    Rosental B, Brusilovsky M, Hadad U, Oz D, Appel MY, Afergan F, Yossef R, Rosenberg LA, Aharoni A, Cerwenka A, Campbell KS, Braiman A, Porgador A (2011) Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44. J Immunol 187(11):5693–5702PubMedGoogle Scholar
  35. 35.
    Stuart-Harris R, Caldas C, Pinder SE, Pharoah P (2008) Proliferation markers and survival in early breast cancer: a systematic review and meta-analysis of 85 studies in 32,825 patients. Breast 17(4):323–334PubMedGoogle Scholar
  36. 36.
    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):159–166PubMedGoogle Scholar
  37. 37.
    Le Maux CB, Moretta A, Vergnon I, Opolon P, Lecluse Y, Grunenwald D, Kubin M, Soria JC, Chouaib S, Mami-Chouaib F (2005) NK cells infiltrating a MHC class I-deficient lung adenocarcinoma display impaired cytotoxic activity toward autologous tumor cells associated with altered NK cell-triggering receptors. J Immunol 175(9):5790–5798Google Scholar
  38. 38.
    Hilpert J, Grosse-Hovest L, Grunebach F, Buechele C, Nuebling T, Raum T, Steinle A, Salih HR (2012) Comprehensive analysis of NKG2D ligand expression and release in leukemia: implications for NKG2D-mediated NK cell responses. J Immunol 189(3):1360–1371PubMedGoogle Scholar
  39. 39.
    Groh V, Wu J, Yee C, Spies T (2002) Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419(6908):734–738PubMedGoogle Scholar
  40. 40.
    Salih HR, Rammensee HG, Steinle A (2002) Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding. J Immunol 169(8):4098–4102PubMedGoogle Scholar
  41. 41.
    Paschen A, Sucker A, Hill B, Moll I, Zapatka M, Nguyen XD, Sim GC, Gutmann I, Hassel J, Becker JC, Steinle A, Schadendorf D, Ugurel S (2009) Differential clinical significance of individual NKG2D ligands in melanoma: soluble ULBP2 as an indicator of poor prognosis superior to S100B. Clin Cancer Res 15(16):5208–5215PubMedGoogle Scholar
  42. 42.
    Coudert JD, Scarpellino L, Gros F, Vivier E, Held W (2008) Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways. Blood 111(7):3571–3578PubMedGoogle Scholar
  43. 43.
    Lee JC, Lee KM, Kim DW, Heo DS (2004) Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol 172(12):7335–7340PubMedGoogle Scholar
  44. 44.
    Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, Biassoni R, Bottino C, Moretta L, Moretta A (2003) Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci U S A 100(7):4120–4125PubMedGoogle Scholar
  45. 45.
    Della Chiesa M, Carlomagno S, Frumento G, Balsamo M, Cantoni C, Conte R, Moretta L, Moretta A, Vitale M (2006) The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood 108(13):4118–4125PubMedGoogle Scholar
  46. 46.
    Pietra G, Manzini C, Rivara S, Vitale M, Cantoni C, Petretto A, Balsamo M, Conte R, Benelli R, Minghelli S, Solari N, Gualco M, Queirolo P, Moretta L, Mingari MC (2012) Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. Cancer Res 72(6):1407–1415PubMedGoogle Scholar
  47. 47.
    Textor S, Fiegler N, Arnold A, Porgador A, Hofmann TG, Cerwenka A (2011) Human NK cells are alerted to induction of p53 in cancer cells by upregulation of the NKG2D ligands ULBP1 and ULBP2. Cancer Res 71(18):5998–6009PubMedGoogle Scholar
  48. 48.
    Liu XV, Ho SS, Tan JJ, Kamran N, Gasser S (2012) Ras activation induces expression of Raet1 family NK receptor ligands. J Immunol 189(4):1826–1834PubMedGoogle Scholar
  49. 49.
    Armeanu S, Bitzer M, Lauer UM, Venturelli S, Pathil A, Krusch M, Kaiser S, Jobst J, Smirnow I, Wagner A, Steinle A, Salih HR (2005) Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res 65(14):6321–6329PubMedGoogle Scholar
  50. 50.
    Kato N, Tanaka J, Sugita J, Toubai T, Miura Y, Ibata M, Syono Y, Ota S, Kondo T, Asaka M, Imamura M (2007) Regulation of the expression of MHC class I-related chain A, B (MICA, MICB) via chromatin remodeling and its impact on the susceptibility of leukemic cells to the cytotoxicity of NKG2D-expressing cells. Leukemia 21(10):2103–2108PubMedGoogle Scholar
  51. 51.
    Heinemann A, Zhao F, Pechlivanis S, Eberle J, Steinle A, Diederichs S, Schadendorf D, Paschen A (2012) Tumor suppressive microRNAs miR-34a/c control cancer cell expression of ULBP2, a stress-induced ligand of the natural killer cell receptor NKG2D. Cancer Res 72(2):460–471PubMedGoogle Scholar
  52. 52.
    Nachmani D, Lankry D, Wolf DG, Mandelboim O (2010) The human cytomegalovirus microRNA miR-UL112 acts synergistically with a cellular microRNA to escape immune elimination. Nat Immunol 11(9):806–813PubMedGoogle Scholar
  53. 53.
    Stern-Ginossar N, Gur C, Biton M, Horwitz E, Elboim M, Stanietsky N, Mandelboim M, Mandelboim O (2008) Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nat Immunol 9(9):1065–1073PubMedGoogle Scholar
  54. 54.
    Hervieu A, Rebe C, Vegran F, Chalmin F, Bruchard M, Vabres P, Apetoh L, Ghiringhelli F, Mignot G (2012) Dacarbazine-mediated upregulation of NKG2D ligands on tumor cells activates NK and CD8 T cells and restrains melanoma growth. J Invest DermatolGoogle Scholar
  55. 55.
    Chavez-Blanco A, De la Cruz-Hernandez E, Dominguez GI, Rodriguez-Cortez O, Alatorre B, Perez-Cardenas E, Chacon-Salinas R, Trejo-Becerril C, Taja-Chayeb L, Trujillo JE, Contreras-Paredes A, Duenas-Gonzalez A (2011) Upregulation of NKG2D ligands and enhanced natural killer cell cytotoxicity by hydralazine and valproate. Int J Oncol 39(6):1491–1499PubMedGoogle Scholar
  56. 56.
    Khallouf H, Marten A, Serba S, Teichgraber V, Buchler MW, Jager D, Schmidt J (2012) 5-Fluorouracil and interferon-alpha immunochemotherapy enhances immunogenicity of murine pancreatic cancer through upregulation of NKG2D ligands and MHC class I. J Immunother 35(3):245–253PubMedGoogle Scholar
  57. 57.
    Lugini L, Cecchetti S, Huber V, Luciani F, Macchia G, Spadaro F, Paris L, Abalsamo L, Colone M, Molinari A, Podo F, Rivoltini L, Ramoni C, Fais S (2012) Immune surveillance properties of human NK cell-derived exosomes. J Immunol 189(6):2833–2842PubMedGoogle Scholar
  58. 58.
    Chauveau A, Aucher A, Eissmann P, Vivier E, Davis DM (2010) Membrane nanotubes facilitate long-distance interactions between natural killer cells and target cells. Proc Natl Acad Sci U S A 107(12):5545–5550PubMedGoogle Scholar
  59. 59.
    Nausch N, Galani IE, Schlecker E, Cerwenka A (2008) Mononuclear myeloid-derived “suppressor” cells express RAE-1 and activate natural killer cells. Blood 112(10):4080–4089PubMedGoogle Scholar
  60. 60.
    Wehner R, Dietze K, Bachmann M, Schmitz M (2011) The bidirectional crosstalk between human dendritic cells and natural killer cells. J Innate Immun 3(3):258–263PubMedGoogle Scholar
  61. 61.
    Rabinovich BA, Li J, Shannon J, Hurren R, Chalupny J, Cosman D, Miller RG (2003) Activated, but not resting, T cells can be recognized and killed by syngeneic NK cells. J Immunol 170(7):3572–3576PubMedGoogle Scholar
  62. 62.
    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(2):95–109PubMedGoogle Scholar
  63. 63.
    Kelly JM, Darcy PK, Markby JL, Godfrey DI, Takeda K, Yagita H, Smyth MJ (2002) Induction of tumor-specific T cell memory by NK cell-mediated tumor rejection. Nat Immunol 3(1):83–90PubMedGoogle Scholar
  64. 64.
    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(12):1260–1265PubMedGoogle Scholar
  65. 65.
    Kelly JM, Takeda K, Darcy PK, Yagita H, Smyth MJ (2002) A role for IFN-gamma in primary and secondary immunity generated by NK cell-sensitive tumor-expressing CD80 in vivo. J Immunol 168(9):4472–4479PubMedGoogle Scholar
  66. 66.
    O’Sullivan T, Saddawi-Konefka R, Vermi W, Koebel CM, Arthur C, White JM, Uppaluri R, Andrews DM, Ngiow SF, Teng MW, Smyth MJ, Schreiber RD, Bui JD (2012) Cancer immunoediting by the innate immune system in the absence of adaptive immunity. J Exp Med 209(10):1869–1882PubMedGoogle Scholar
  67. 67.
    Maghazachi AA (2010) Role of chemokines in the biology of natural killer cells. Curr Top Microbiol Immunol 341:37–58PubMedGoogle Scholar
  68. 68.
    Terabe M, Park JM, Berzofsky JA (2004) Role of IL-13 in regulation of anti-tumor immunity and tumor growth. Cancer Immunol Immunother 53(2):79–85PubMedGoogle Scholar
  69. 69.
    Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, Carson WE, Caligiuri MA (2001) Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood 97(10):3146–3151PubMedGoogle Scholar
  70. 70.
    Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R (2011) Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res 17(22):6985–6991PubMedGoogle Scholar
  71. 71.
    Kim HS, Moon HG, Han W, Yom CK, Kim WH, Kim JH, Noh DY (2012) COX2 overexpression is a prognostic marker for Stage III breast cancer. Breast Cancer Res Treat 132(1):51–59PubMedGoogle Scholar
  72. 72.
    Amiot L, Ferrone S, Grosse-Wilde H, Seliger B (2011) Biology of HLA-G in cancer: a candidate molecule for therapeutic intervention? Cell Mol Life Sci 68(3):417–431PubMedGoogle Scholar
  73. 73.
    Borrego F, Kabat J, Kim DK, Lieto L, Maasho K, Pena J, Solana R, Coligan JE (2002) Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells. Mol Immunol 38(9):637–660PubMedGoogle Scholar
  74. 74.
    Zilberman S, Schenowitz C, Agaugue S, Benoit F, Riteau B, Rouzier R, Carosella ED, Rouas-Freiss N, Menier C (2012) HLA-G1 and HLA-G5 active dimers are present in malignant cells and effusions: the influence of the tumor microenvironment. Eur J Immunol 42(6):1599–1608PubMedGoogle Scholar
  75. 75.
    Campoli M, Ferrone S (2008) Tumor escape mechanisms: potential role of soluble HLA antigens and NK cells activating ligands. Tissue Antigens 72(4):321–334PubMedGoogle Scholar
  76. 76.
    Rouas-Freiss N, Moreau P, Menier C, LeMaoult J, Carosella ED (2007) Expression of tolerogenic HLA-G molecules in cancer prevents antitumor responses. Semin Cancer Biol 17(6):413–421PubMedGoogle Scholar
  77. 77.
    Frey AB, Monu N (2008) Signaling defects in anti-tumor T cells. Immunol Rev 222:192–205PubMedGoogle Scholar
  78. 78.
    Wherry EJ (2011) T cell exhaustion. Nat Immunol 12(6):492–499PubMedGoogle Scholar
  79. 79.
    Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA (2009) Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114(8):1537–1544PubMedGoogle Scholar
  80. 80.
    Zippelius A, Batard P, Rubio-Godoy V, Bioley G, Lienard D, Lejeune F, Rimoldi D, Guillaume P, Meidenbauer N, Mackensen A, Rufer N, Lubenow N, Speiser D, Cerottini JC, Romero P, Pittet MJ (2004) Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res 64(8):2865–2873PubMedGoogle Scholar
  81. 81.
    Terme M, Ullrich E, Aymeric L, Meinhardt K, Desbois M, Delahaye N, Viaud S, Ryffel B, Yagita H, Kaplanski G, Prevost-Blondel A, Kato M, Schultze JL, Tartour E, Kroemer G, Chaput N, Zitvogel L (2011) IL-18 induces PD-1-dependent immunosuppression in cancer. Cancer Res 71(16):5393–5399PubMedGoogle Scholar
  82. 82.
    Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, Baiocchi RA, Zhang J, Yu J, Smith MK, Greenfield CN, Porcu P, Devine SM, Rotem-Yehudar R, Lozanski G, Byrd JC, Caligiuri MA (2010) The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 116(13):2286–2294PubMedGoogle Scholar
  83. 83.
    Bour-Jordan H, Esensten JH, Martinez-Llordella M, Penaranda C, Stumpf M, Bluestone JA (2011) Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family. Immunol Rev 241(1):180–205PubMedGoogle Scholar
  84. 84.
    Miyazaki T, Dierich A, Benoist C, Mathis D (1996) Independent modes of natural killing distinguished in mice lacking Lag3. Science 272(5260):405–408PubMedGoogle Scholar
  85. 85.
    Le Bouteiller P, Tabiasco J, Polgar B, Kozma N, Giustiniani J, Siewiera J, Berrebi A, Aguerre-Girr M, Bensussan A, Jabrane-Ferrat N (2011) CD160: a unique activating NK cell receptor. Immunol Lett 138(2):93–96PubMedGoogle Scholar
  86. 86.
    Cai G, Freeman GJ (2009) The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation. Immunol Rev 229(1):244–258PubMedGoogle Scholar
  87. 87.
    Ndhlovu LC, Lopez-Verges S, Barbour JD, Jones RB, Jha AR, Long BR, Schoeffler EC, Fujita T, Nixon DF, Lanier LL (2012) Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood 119(16):3734–3743PubMedGoogle Scholar
  88. 88.
    Gleason MK, Lenvik TR, McCullar V, Felices M, O’Brien MS, Cooley SA, Verneris MR, Cichocki F, Holman CJ, Panoskaltsis-Mortari A, Niki T, Hirashima M, Blazar BR, Miller JS (2012) Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9. Blood 119(13):3064–3072PubMedGoogle Scholar
  89. 89.
    Lai P, Rabinowich H, Crowley-Nowick PA, Bell MC, Mantovani G, Whiteside TL (1996) Alterations in expression and function of signal-transducing proteins in tumor-associated T and natural killer cells in patients with ovarian carcinoma. Clin Cancer Res 2(1):161–173PubMedGoogle Scholar
  90. 90.
    Rabinowich H, Suminami Y, Reichert TE, Crowley-Nowick P, Bell M, Edwards R, Whiteside TL (1996) Expression of cytokine genes or proteins and signaling molecules in lymphocytes associated with human ovarian carcinoma. Int J Cancer 68(3):276–284PubMedGoogle Scholar
  91. 91.
    Moretta L, Ferlazzo G, Bottino C, Vitale M, Pende D, Mingari MC, Moretta A (2006) Effector and regulatory events during natural killer-dendritic cell interactions. Immunol Rev 214:219–228PubMedGoogle Scholar
  92. 92.
    Bell D, Chomarat P, Broyles D, Netto G, Harb GM, Lebecque S, Valladeau J, Davoust J, Palucka KA, Banchereau J (1999) In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med 190(10):1417–1426Google Scholar
  93. 93.
    Hurwitz AA, Watkins SK (2012) Immune suppression in the tumor microenvironment: a role for dendritic cell-mediated tolerization of T cells. Cancer Immunol Immunother 61(2):289–293Google Scholar
  94. 94.
    Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174PubMedGoogle Scholar
  95. 95.
    Li H, Han Y, Guo Q, Zhang M, Cao X (2009) Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol 182(1):240–249PubMedGoogle Scholar
  96. 96.
    Smyth MJ, Teng MW, Swann J, Kyparissoudis K, Godfrey DI, Hayakawa Y (2006) CD4+ CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J Immunol 176(3):1582–1587PubMedGoogle Scholar
  97. 97.
    Ghiringhelli F, Menard C, Terme M, Flament C, Taieb J, Chaput N, Puig PE, Novault S, Escudier B, Vivier E, Lecesne A, Robert C, Blay JY, Bernard J, Caillat-Zucman S, Freitas A, Tursz T, Wagner-Ballon O, Capron C, Vainchencker W, Martin F, Zitvogel L (2005) CD4+ CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med 202(8):1075–1085PubMedGoogle Scholar
  98. 98.
    Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limon P (2010) The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol 10(8):554–567PubMedGoogle Scholar
  99. 99.
    Textor S, Durst M, Jansen L, Accardi R, Tommasino M, Trunk MJ, Porgador A, Watzl C, Gissmann L, Cerwenka A (2008) Activating NK cell receptor ligands are differentially expressed during progression to cervical cancer. Int J Cancer 123(10):2343–2353PubMedGoogle Scholar
  100. 100.
    Schleypen JS, Baur N, Kammerer R, Nelson PJ, Rohrmann K, Grone EF, Hohenfellner M, Haferkamp A, Pohla H, Schendel DJ, Falk CS, Noessner E (2006) Cytotoxic markers and frequency predict functional capacity of natural killer cells infiltrating renal cell carcinoma. Clin Cancer Res 12(3 Pt 1):718–725PubMedGoogle Scholar
  101. 101.
    Patankar MS, Jing Y, Morrison JC, Belisle JA, Lattanzio FA, Deng Y, Wong NK, Morris HR, Dell A, Clark GF (2005) Potent suppression of natural killer cell response mediated by the ovarian tumor marker CA125. Gynecol Oncol 99(3):704–713PubMedGoogle Scholar
  102. 102.
    Harlin H, Hanson M, Johansson CC, Sakurai D, Poschke I, Norell H, Malmberg KJ, Kiessling R (2007) The CD16- CD56(bright) NK cell subset is resistant to reactive oxygen species produced by activated granulocytes and has higher antioxidative capacity than the CD16+ CD56(dim) subset. J Immunol 179(7):4513–4519PubMedGoogle Scholar
  103. 103.
    Wendel M, Galani IE, Suri-Payer E, Cerwenka A (2008) Natural killer cell accumulation in tumors is dependent on IFN-gamma and CXCR3 ligands. Cancer Res 68(20):8437–8445PubMedGoogle Scholar
  104. 104.
    Bjorkstrom NK, Riese P, Heuts F, Andersson S, Fauriat C, Ivarsson MA, Bjorklund AT, Flodstrom-Tullberg M, Michaelsson J, Rottenberg ME, Guzman CA, Ljunggren HG, Malmberg KJ (2010) Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK cell differentiation uncoupled from NK cell education. Blood 116(19):3853–3864PubMedGoogle Scholar
  105. 105.
    Lopez-Verges S, Milush JM, Pandey S, York VA, Arakawa-Hoyt J, Pircher H, Norris PJ, Nixon DF, Lanier LL (2010) CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK cell subset. Blood 116(19):3865–3874PubMedGoogle Scholar
  106. 106.
    Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, Iwashige H, Aridome K, Hokita S, Aikou T (2000) Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 88(3):577–583PubMedGoogle Scholar
  107. 107.
    Villegas FR, Coca S, Villarrubia VG, Jimenez R, Chillon MJ, Jareno J, Zuil M, Callol L (2002) Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. Lung Cancer 35(1):23–28PubMedGoogle Scholar
  108. 108.
    Schleypen JS, Von Geldern M, Weiss EH, Kotzias N, Rohrmann K, Schendel DJ, Falk CS, Pohla H (2003) Renal cell carcinoma-infiltrating natural killer cells express differential repertoires of activating and inhibitory receptors and are inhibited by specific HLA class I allotypes. Int J Cancer 106(6):905–912PubMedGoogle Scholar
  109. 109.
    Esendagli G, Bruderek K, Goldmann T, Busche A, Branscheid D, Vollmer E, Brandau S (2008) Malignant and non-malignant lung tissue areas are differentially populated by natural killer cells and regulatory T cells in non-small cell lung cancer. Lung Cancer 59(1):32–40PubMedGoogle Scholar
  110. 110.
    Sandel MH, Speetjens FM, Menon AG, Albertsson PA, Basse PH, Hokland M, Nagelkerke JF, Tollenaar RA, van de Velde CJ, Kuppen PJ (2005) Natural killer cells infiltrating colorectal cancer and MHC class I expression. Mol Immunol 42(4):541–546PubMedGoogle Scholar
  111. 111.
    Albertsson PA, Basse PH, Hokland M, Goldfarb RH, Nagelkerke JF, Nannmark U, Kuppen PJ (2003) NK cells and the tumour microenvironment: implications for NK-cell function and anti-tumour activity. Trends Immunol 24(11):603–609PubMedGoogle Scholar
  112. 112.
    Hayakawa Y, Huntington ND, Nutt SL, Smyth MJ (2006) Functional subsets of mouse natural killer cells. Immunol Rev 214:47–55PubMedGoogle Scholar
  113. 113.
    Lavergne E, Combadiere B, Bonduelle O, Iga M, Gao JL, Maho M, Boissonnas A, Murphy PM, Debre P, Combadiere C (2003) Fractalkine mediates natural killer-dependent antitumor responses in vivo. Cancer Res 63(21):7468–7474PubMedGoogle Scholar
  114. 114.
    Pachynski RK, Zabel BA, Kohrt HE, Tejeda NM, Monnier J, Swanson CD, Holzer AK, Gentles AJ, Sperinde GV, Edalati A, Hadeiba HA, Alizadeh AA, Butcher EC (2012) The chemoattractant chemerin suppresses melanoma by recruiting natural killer cell antitumor defenses. J Exp Med 209(8):1427–1435PubMedGoogle Scholar
  115. 115.
    Blobel CP (2005) ADAMs: key components in EGFR signalling and development. Nat Rev Mol Cell Biol 6(1):32–43PubMedGoogle Scholar
  116. 116.
    Reiss K, Ludwig A, Saftig P (2006) Breaking up the tie: disintegrin-like metalloproteinases as regulators of cell migration in inflammation and invasion. Pharmacol Ther 111(3):985–1006PubMedGoogle Scholar
  117. 117.
    White JM (2003) ADAMs: modulators of cell-cell and cell-matrix interactions. Curr Opin Cell Biol 15(5):598–606PubMedGoogle Scholar
  118. 118.
    Waldhauer I, Goehlsdorf D, Gieseke F, Weinschenk T, Wittenbrink M, Ludwig A, Stevanovic S, Rammensee HG, Steinle A (2008) Tumor-associated MICA is shed by ADAM proteases. Cancer Res 68(15):6368–6376PubMedGoogle Scholar
  119. 119.
    Boutet P, Aguera-Gonzalez S, Atkinson S, Pennington CJ, Edwards DR, Murphy G, Reyburn HT, Vales-Gomez M (2009) Cutting edge: the metalloproteinase ADAM17/TNF-alpha-converting enzyme regulates proteolytic shedding of the MHC class I-related chain B protein. J Immunol 182(1):49–53PubMedGoogle Scholar
  120. 120.
    Grzywacz B, Kataria N, Verneris MR (2007) CD56(dim)CD16(+) NK cells downregulate CD16 following target cell induced activation of matrix metalloproteinases. Leukemia 21(2):356–359, author reply 359PubMedGoogle Scholar
  121. 121.
    Imai K, Matsuyama S, Miyake S, Suga K, Nakachi K (2000) Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet 356(9244):1795–1799PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Ana Stojanovic
    • 1
  • Margareta P. Correia
    • 1
  • Adelheid Cerwenka
    • 1
    • 2
  1. 1.Innate Immunity, German Cancer Research CenterHeidelbergGermany
  2. 2.“Innate Immunity”/D080German Cancer Research CenterHeidelbergGermany

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