Abstract
Natural killer (NK) cell activation is strictly regulated to ensure that healthy cells are preserved, but tumour-transformed or virus-infected cells are recognized and eliminated. To carry out this selective killing, NK cells have an ample repertoire of receptors on their surface. Signalling by inhibitory and activating receptors by interaction with their ligands will determine whether the NK cell becomes activated and kills the target cell. Here, we show reduced expression of NKp46, NKp30, DNAM-1, CD244 and CD94/NKG2C activating receptors on NK cells from acute myeloid leukaemia patients. This reduction may be induced by chronic exposure to their ligands on leukaemic blasts. The analysis of ligands for NK cell-activating receptors showed that leukaemic blasts from the majority of patients express ligands for NK cell-activating receptors. DNAM-1 ligands are frequently expressed on blasts, whereas the expression of the NKG2D ligand MICA/B is found in half of the patients and CD48, a ligand for CD244, in only one-fourth of the patients. The decreased expression of NK cell-activating receptors and/or the heterogeneous expression of ligands for major receptors on leukaemic blasts can lead to an inadequate tumour immunosurveillance by NK cells. A better knowledge of the activating receptor repertoire on NK cells and their putative ligands on blasts together with the possibility to modulate their expression will open new possibilities for the use of NK cells in immunotherapy against leukaemia.



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Anfossi N, Andre P, Guia S, Falk CS, Roetynck S, Stewart CA, Breso V, Frassati C, Reviron D, Middleton D, Romagne F, Ugolini S, Vivier E (2006) Human NK cell education by inhibitory receptors for MHC class I. Immunity 25:331–342
Bjorkstrom NK, Ljunggren HG, Sandberg JK (2010) CD56 negative NK cells: origin, function, and role in chronic viral disease. Trends Immunol 31:401–406
Boles KS, Stepp SE, Bennett M, Kumar V, Mathew PA (2001) 2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes. Immunol Rev 181:234–249
Borrego F, Masilamani M, Marusina AI, Tang X, Coligan JE (2006) The CD94/NKG2 family of receptors: from molecules and cells to clinical relevance. Immunol Res 35:263–278
Bottino C, Castriconi R, Pende D, Rivera P, Nanni M, Carnemolla B, Cantoni C, Grassi J, Marcenaro S, Reymond N, Vitale M, Moretta L, Lopez M, Moretta A (2003) Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med 198:557–567
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 206:1495–1503
Braun M, Muller B, Ter MD, Raffegerst S, Simm B, Wilde S, Spranger S, Ellwart J, Mosetter B, Umansky L, Lerchl T, Schendel DJ, Falk CS (2010) The CD6 scavenger receptor is differentially expressed on a CD56 natural killer cell subpopulation and contributes to natural killer-derived cytokine and chemokine secretion. J Innate Immun E-pub ahead of print
Bryceson YT, Long EO (2008) Line of attack: NK cell specificity and integration of signals. Curr Opin Immunol 20:344–352
Burgess SJ, Maasho K, Masilamani M, Narayanan S, Borrego F, Coligan JE (2008) The NKG2D receptor: immunobiology and clinical implications. Immunol Res 40:18–34
Campbell KS, Purdy AK (2011) Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations. Immunology 132:315–325
Carlsten M, Baumann BC, Simonsson M, Jadersten M, Forsblom AM, Hammarstedt C, Bryceson YT, Ljunggren HG, Hellstrom-Lindberg E, Malmberg KJ (2010) Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome. Leukemia 24:1607–1616
Carlsten M, Norell H, Bryceson YT, Poschke I, Schedvins K, Ljunggren HG, Kiessling R, Malmberg KJ (2009) Primary human tumor cells expressing CD155 impair tumor targeting by down-regulating DNAM-1 on NK cells. J Immunol 183:4921–4930
Casado JG, Pawelec G, Morgado S, Sanchez-Correa B, Delgado E, Gayoso I, Duran E, Solana R, Tarazona R (2009) Expression of adhesion molecules and ligands for activating and costimulatory receptors involved in cell-mediated cytotoxicity in a large panel of human melanoma cell lines. Cancer Immunol Immunother 58:1517–1526
Champsaur M, Lanier LL (2010) Effect of NKG2D ligand expression on host immune responses. Immunol Rev 235:267–285
Chan A, Hong DL, Atzberger A, Kollnberger S, Filer AD, Buckley CD, McMichael A, Enver T, Bowness P (2007) CD56bright human NK cells differentiate into CD56dim cells: role of contact with peripheral fibroblasts. J Immunol 179:89–94
Costello RT, Sivori S, Marcenaro E, Lafage-Pochitaloff M, Mozziconacci MJ, Reviron D, Gastaut JA, Pende D, Olive D, Moretta A (2002) Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia. Blood 99:3661–3667
Derhovanessian E, Solana R, Larbi A, Pawelec G (2008) Immunity, ageing and cancer. Immun Ageing 5:11
Diermayr S, Himmelreich H, Durovic B, Mathys-Schneeberger A, Siegler U, Langenkamp U, Hofsteenge J, Gratwohl A, Tichelli A, Paluszewska M, Wiktor-Jedrzejczak W, Kalberer CP, Wodnar-Filipowicz A (2008) NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities. Blood 111:1428–1436
Eagle RA, Trowsdale J (2007) Promiscuity and the single receptor: NKG2D. Nat Rev Immunol 7:737–744
El-Sherbiny YM, Meade JL, Holmes TD, McGonagle D, Mackie SL, Morgan AW, Cook G, Feyler S, Richards SJ, Davies FE, Morgan GJ, Cook GP (2007) The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells. Cancer Res 67:8444–8449
Elishmereni M, Levi-Schaffer F (2011) CD48: a co-stimulatory receptor of immunity. Int J Biochem Cell Biol 43:25–28
Epling-Burnette PK, Bai F, Painter JS, Rollison DE, Salih HR, Krusch M, Zou J, Ku E, Zhong B, Boulware D, Moscinski L, Wei S, Djeu JY, List AF (2007) Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors. Blood 109:4816–4824
Farag SS, Caligiuri MA (2006) Human natural killer cell development and biology. Blood Rev 20:123–137
Fauriat C, Just-Landi S, Mallet F, Arnoulet C, Sainty D, Olive D, Costello RT (2007) Deficient expression of NCR in NK cells from acute myeloid leukemia: Evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction. Blood 109:323–330
Gayoso I, Sanchez-Correa B, Campos C, Alonso C, Pera A, Casado JG, Morgado S, Tarazona R, Solana R (2011) Immunosenescence of human natural killer cells. J Innate Immun E-pub ahead of print
Gilfillan S, Chan CJ, Cella M, Haynes NM, Rapaport AS, Boles KS, Andrews DM, Smyth MJ, Colonna M (2008) DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors. J Exp Med 205:2965–2973
Groh V, Wu J, Yee C, Spies T (2002) Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419:734–738
Hecht ML, Rosental B, Horlacher T, Hershkovitz O, De Paz JL, Noti C, Schauer S, Porgador A, Seeberger PH (2009) Natural cytotoxicity receptors NKp30, NKp44 and NKp46 bind to different heparan sulfate/heparin sequences. J Proteome Res 8:712–720
Held W, Kijima M, Angelov GS, Bessoles S (2011) The function of natural killer cells: education, reminders and some good memories. Curr Opin Immunol 23:228–233
Jabbour EJ, Estey E, Kantarjian HM (2006) Adult acute myeloid leukemia. Mayo Clin Proc 81:247–260
Kalinski P, Mailliard RB, Giermasz A, Zeh HJ, Basse P, Bartlett DL, Kirkwood JM, Lotze MT, Herberman RB (2005) Natural killer-dendritic cell cross-talk in cancer immunotherapy. Expert Opin Biol Ther 5:1303–1315
Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, Song YJ, Yang L, French AR, Sunwoo JB, Lemieux S, Hansen TH, Yokoyama WM (2005) Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436:709–713
Lakshmikanth T, Burke S, Ali TH, Kimpfler S, Ursini F, Ruggeri L, Capanni M, Umansky V, Paschen A, Sucker A, Pende D, Groh V, Biassoni R, Hoglund P, Kato M, Shibuya K, Schadendorf D, Anichini A, Ferrone S, Velardi A, Karre K, Shibuya A, Carbone E, Colucci F (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
Ljunggren HG, Karre K (1990) In search of the ‘missing self: MHC molecules and NK cell recognition. Immunol Today 11:237–244
Malmberg KJ, Bryceson YT, Carlsten M, Andersson S, Bjorklund A, Bjorkstrom NK, Baumann BC, Fauriat C, Alici E, Dilber MS, Ljunggren HG (2008) NK cell-mediated targeting of human cancer and possibilities for new means of immunotherapy. Cancer Immunol Immunother 57:1541–1552
Mathew SO, Rao KK, Kim JR, Bambard ND, Mathew PA (2009) Functional role of human NK cell receptor 2B4 (CD244) isoforms. Eur J Immunol 39:1632–1641
Mavilio D, Lombardo G, Benjamin J, Kim D, Follman D, Marcenaro E, O’Shea MA, Kinter A, Kovacs C, Moretta A, Fauci AS (2005) Characterization of CD56−/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc Natl Acad Sci USA 102:2886–2891
McGilvray RW, Eagle RA, Watson NF, Al-Attar A, Ball G, Jafferji I, Trowsdale J, Durrant LG (2009) NKG2D ligand expression in human colorectal cancer reveals associations with prognosis and evidence for immunoediting. Clin Cancer Res 15:6993–7002
McNerney ME, Lee KM, Kumar V (2005) 2B4 (CD244) is a non-MHC binding receptor with multiple functions on natural killer cells and CD8+ T cells. Mol Immunol 42:489–494
Mendez R, Aptsiauri N, Del CA, Maleno I, Cabrera T, Ruiz-Cabello F, Garrido F, Garcia-Lora A (2009) HLA and melanoma: multiple alterations in HLA class I and II expression in human melanoma cell lines from ESTDAB cell bank. Cancer Immunol Immunother 58:1507–1515
Morgado S, Sanchez-Correa B, Casado JG, Duran E, Gayoso I, Labella F, Solana R, Tarazona R (2011) NK cell recognition and killing of melanoma cells is controlled by multiple activating receptor-ligand interactions. J Innate Immun E-pub ahead of print
Naumova E, Mihaylova A, Ivanova M, Mihailova S (2007) Impact of KIR/HLA ligand combinations on immune responses in malignant melanoma. Cancer Immunol Immunother 56:95–100
Nguyen S, Beziat V, Roos-Weil D, Vieillard V (2011) Role of natural killer cells in hematopoietic stem cell transplantation: myth or reality? J Innate Immun E-pub ahead of print
Nowbakht P, Ionescu MC, Rohner A, Kalberer CP, Rossy E, Mori L, Cosman D, De LG, Wodnar-Filipowicz A (2005) Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias. Blood 105:3615–3622
Ofori-Acquah SF, King JA (2008) Activated leukocyte cell adhesion molecule: a new paradox in cancer. Transl Res 151:122–128
Orr MT, Lanier LL (2010) Natural killer cell education and tolerance. Cell 142:847–856
Pawelec G, Solana R (2008) Are cancer and ageing different sides of the same coin? Conference on Cancer and Ageing. EMBO Rep 9:234–238
Pende D, Bottino C, Castriconi R, Cantoni C, Marcenaro S, Rivera P, Spaggiari GM, Dondero A, Carnemolla B, Reymond N, Mingari MC, Lopez M, Moretta L, Moretta A (2005) PVR (CD155) and Nectin-2 (CD112) as ligands of the human DNAM-1 (CD226) activating receptor: involvement in tumor cell lysis. Mol Immunol 42:463–469
Pende D, Cantoni C, Rivera P, Vitale M, Castriconi R, Marcenaro S, Nanni M, Biassoni R, Bottino C, Moretta A, Moretta L (2001) 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. Eur J Immunol 31:1076–1086
Pende D, Spaggiari GM, Marcenaro S, Martini S, Rivera P, Capobianco A, Falco M, Lanino E, Pierri I, Zambello R, Bacigalupo A, Mingari MC, Moretta A, Moretta L (2005) Analysis of the receptor-ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the Poliovirus receptor (CD155) and Nectin-2 (CD112). Blood 105:2066–2073
Peralbo E, DelaRosa O, Gayoso I, Pita ML, Tarazona R, Solana R (2006) Decreased frequency and proliferative response of invariant Valpha24Vbeta11 natural killer T (iNKT) cells in healthy elderly. Biogerontology 7:483–492
von Pogge SE, 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 27:965–974
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 295:2097–2100
Salih HR, Antropius H, Gieseke F, Lutz SZ, Kanz L, Rammensee HG, Steinle A (2003) Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood 102:1389–1396
Salih HR, Holdenrieder S, Steinle A (2008) Soluble NKG2D ligands: prevalence, release, and functional impact. Front Biosci 13:3448–3456
Sanchez CJ, Le TT, Boehrer A, Knoblauch B, Imbert J, Olive D, Costello RT (2011) Natural killer cells and malignant haemopathies: a model for the interaction of cancer with innate immunity. Cancer Immunol Immunother 60:1–13
Sanchez-Correa B, Gayoso I, Bergua JM, Casado JG, Morgado S, Solana R, Tarazona R (2011) Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients. Immunol Cell Biol E-pub ahead of print
Sivori S, Parolini S, Falco M, Marcenaro E, Biassoni R, Bottino C, Moretta L, Moretta A (2000) 2B4 functions as a co-receptor in human NK cell activation. Eur J Immunol 30:787–793
Solana R, Casado JG, Delgado E, DelaRosa O, Marin J, Duran E, Pawelec G, Tarazona R (2007) Lymphocyte activation in response to melanoma: interaction of NK-associated receptors and their ligands. Cancer Immunol Immunother 56:101–109
Solana R, Pawelec G, Tarazona R (2006) Aging and innate immunity. Immunity 24:491–494
Sun JC, Beilke JN, Lanier LL (2009) Adaptive immune features of natural killer cells. Nature 457:557–561
Szczepanski MJ, Szajnik M, Welsh A, Foon KA, Whiteside TL, Boyiadzis M (2010) Interleukin-15 enhances natural killer cell cytotoxicity in patients with acute myeloid leukemia by upregulating the activating NK cell receptors. Cancer Immunol Immunother 59:73–79
Tahara-Hanaoka S, Shibuya K, Kai H, Miyamoto A, Morikawa Y, Ohkochi N, Honda S, Shibuya A (2006) Tumor rejection by the poliovirus receptor family ligands of the DNAM-1 (CD226) receptor. Blood 107:1491–1496
Tarazona R, Casado JG, DelaRosa O, Torre-Cisneros J, Villanueva JL, Sanchez B, Galiani MD, Gonzalez R, Solana R, Pena J (2002) Selective depletion of CD56(dim) NK cell subsets and maintenance of CD56(bright) NK cells in treatment-naive HIV-1-seropositive individuals. J Clin Immunol 22:176–183
Tripathy SK, Keyel PA, Yang L, Pingel JT, Cheng TP, Schneeberger A, Yokoyama WM (2008) Continuous engagement of a self-specific activation receptor induces NK cell tolerance. J Exp Med 205:1829–1841
Vaidya SV, Mathew PA (2006) Of mice and men: different functions of the murine and human 2B4 (CD244) receptor on NK cells. Immunol Lett 105:180–184
Velardi A, Ruggeri L, Moretta A, Moretta L (2002) NK cells: a lesson from mismatched hematopoietic transplantation. Trends Immunol 23:438–444
Verheyden S, Bernier M, Demanet C (2004) Identification of natural killer cell receptor phenotypes associated with leukemia. Leukemia 18:2002–2007
Verheyden S, Demanet C (2006) Susceptibility to myeloid and lymphoid leukemia is mediated by distinct inhibitory KIR-HLA ligand interactions. Leukemia 20:1437–1438
Verheyden S, Demanet C (2008) NK cell receptors and their ligands in leukemia. Leukemia 22:249–257
Verheyden S, Ferrone S, Mulder A, Claas FH, Schots R, De Moerloose B, Benoit Y, Demanet C (2009) Role of the inhibitory KIR ligand HLA-Bw4 and HLA-C expression levels in the recognition of leukemic cells by natural Killer cells. Cancer Immunol Immunother 58:855–865
Verneris MR, Miller JS (2009) The phenotypic and functional characteristics of umbilical cord blood and peripheral blood natural killer cells. Br J Haematol 147:185–191
Vivier E, Nunes JA, Vely F (2004) Natural killer cell signaling pathways. Science 306:1517–1519
Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM, Ugolini S (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331:44–49
Waldhauer I, Steinle A (2008) NK cells and cancer immunosurveillance. Oncogene 27:5932–5943
Wehner R, Dietze K, Bachmann M, Schmitz M (2011) The bidirectional crosstalk between human dendritic cells and natural killer cells. J Innate Immun E-pub ahead of print
Acknowledgments
We apologize to our colleagues whose work was not cited due to space limitations. This work was supported by grants SAF2006-03687 and SAF2009-09711 (to RT) from the Ministry of Science and Innovation of Spain, FIS PI061320 and PS09/00723 (to R.S.) from Spanish Ministry of Health, PRI09A029 and grants to INPATT research group from Junta de Extremadura (GRU08077, GRU09156 and GRU10104) and from University of Extremadura, cofinanced by European Regional Development Fund (FEDER). BSC is a postdoctoral fellow supported by grant ACCIII/22 from University of Extremadura Spain, and SM is a predoctoral fellow supported by grant PRE07047 from Junta de Extremadura. We thank J.J. Gordillo and M.R. Gonzalez and for their technical assistance in cell culture and flow cytometry.
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Beatriz Sanchez-Correa and Sara Morgado contributed equally to the manuscript.
This paper is a Focussed Research Review based on a presentation given at the Tenth International Conference on Progress in Vaccination against Cancer (PIVAC 10), held in St. Catharine’s College, Cambridge, UK, 27th–30th September 2010. It is part of a CII series of Focussed Research Reviews and meeting report.
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Sanchez-Correa, B., Morgado, S., Gayoso, I. et al. Human NK cells in acute myeloid leukaemia patients: analysis of NK cell-activating receptors and their ligands. Cancer Immunol Immunother 60, 1195–1205 (2011). https://doi.org/10.1007/s00262-011-1050-2
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DOI: https://doi.org/10.1007/s00262-011-1050-2
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