Skip to main content
Erschienen in: Cancer Microenvironment 2/2013

01.08.2013 | Original Article

Shaping of NK Cell Responses by the Tumor Microenvironment

verfasst von: Ana Stojanovic, Margareta P. Correia, Adelheid Cerwenka

Erschienen in: Cancer Microenvironment | Ausgabe 2/2013

Einloggen, um Zugang zu erhalten

Abstract

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.
Literatur
1.
Zurück zum Zitat 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 11:19PubMed 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 11:19PubMed
2.
Zurück zum Zitat 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):2320–2328PubMed 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):2320–2328PubMed
3.
Zurück zum Zitat Kerkar SP, Restifo NP (2012) Cellular constituents of immune escape within the tumor microenvironment. Cancer Res 72(13):3125–3130PubMed Kerkar SP, Restifo NP (2012) Cellular constituents of immune escape within the tumor microenvironment. Cancer Res 72(13):3125–3130PubMed
4.
Zurück zum Zitat Facciabene A, Motz GT, Coukos G (2012) T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res 72(9):2162–2171PubMed Facciabene A, Motz GT, Coukos G (2012) T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res 72(9):2162–2171PubMed
5.
Zurück zum Zitat Nagaraj S, Gabrilovich DI (2008) Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res 68(8):2561–2563PubMed Nagaraj S, Gabrilovich DI (2008) Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res 68(8):2561–2563PubMed
6.
Zurück zum Zitat Bryceson YT, Long EO (2008) Line of attack: NK cell specificity and integration of signals. Curr Opin Immunol 20(3):344–352PubMed Bryceson YT, Long EO (2008) Line of attack: NK cell specificity and integration of signals. Curr Opin Immunol 20(3):344–352PubMed
7.
Zurück zum Zitat 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):103–109PubMed 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):103–109PubMed
8.
Zurück zum Zitat 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):2097–2100PubMed 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):2097–2100PubMed
9.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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):805–816PubMed 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):805–816PubMed
12.
Zurück zum Zitat 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):486–494PubMed 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):486–494PubMed
13.
Zurück zum Zitat Andrews DM, Maraskovsky E, Smyth MJ (2008) Cancer vaccines for established cancer: how to make them better? Immunol Rev 222:242–255PubMed Andrews DM, Maraskovsky E, Smyth MJ (2008) Cancer vaccines for established cancer: how to make them better? Immunol Rev 222:242–255PubMed
14.
Zurück zum Zitat Alderson KL, Sondel PM (2011) Clinical cancer therapy by NK cells via antibody-dependent cell-mediated cytotoxicity. J Biomed Biotechnol 2011:379123PubMed Alderson KL, Sondel PM (2011) Clinical cancer therapy by NK cells via antibody-dependent cell-mediated cytotoxicity. J Biomed Biotechnol 2011:379123PubMed
15.
Zurück zum Zitat 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):117–121PubMed 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):117–121PubMed
16.
Zurück zum Zitat 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):112–117PubMed 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):112–117PubMed
17.
Zurück zum Zitat Bryceson YT, March ME, Ljunggren HG, Long EO (2006) Activation, coactivation, and costimulation of resting human natural killer cells. Immunol Rev 214:73–91PubMed Bryceson YT, March ME, Ljunggren HG, Long EO (2006) Activation, coactivation, and costimulation of resting human natural killer cells. Immunol Rev 214:73–91PubMed
18.
Zurück zum Zitat 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):503–517PubMed 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):503–517PubMed
19.
Zurück zum Zitat 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):2174–2181PubMed 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):2174–2181PubMed
20.
Zurück zum Zitat Sporri R, Joller N, Hilbi H, Oxenius A (2008) A novel role for neutrophils as critical activators of NK cells. J Immunol 181(10):7121–7130PubMed Sporri R, Joller N, Hilbi H, Oxenius A (2008) A novel role for neutrophils as critical activators of NK cells. J Immunol 181(10):7121–7130PubMed
21.
Zurück zum Zitat 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):565–580PubMed 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):565–580PubMed
22.
Zurück zum Zitat Zwirner NW, Domaica CI (2010) Cytokine regulation of natural killer cell effector functions. Biofactors 36(4):274–288PubMed Zwirner NW, Domaica CI (2010) Cytokine regulation of natural killer cell effector functions. Biofactors 36(4):274–288PubMed
23.
Zurück zum Zitat Nausch N, Cerwenka A (2008) NKG2D ligands in tumor immunity. Oncogene 27(45):5944–5958PubMed Nausch N, Cerwenka A (2008) NKG2D ligands in tumor immunity. Oncogene 27(45):5944–5958PubMed
24.
Zurück zum Zitat Raulet DH (2003) Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 3(10):781–790PubMed Raulet DH (2003) Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 3(10):781–790PubMed
25.
Zurück zum Zitat Raulet DH, Guerra N (2009) Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat Rev Immunol 9(8):568–580PubMed Raulet DH, Guerra N (2009) Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat Rev Immunol 9(8):568–580PubMed
26.
Zurück zum Zitat 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):3503–3511PubMed 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):3503–3511PubMed
27.
Zurück zum Zitat 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):902–911PubMed 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):902–911PubMed
28.
Zurück zum Zitat 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):1325–1335PubMed 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):1325–1335PubMed
29.
Zurück zum Zitat 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):571–580PubMed 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):571–580PubMed
30.
Zurück zum Zitat 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):965–974PubMed 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):965–974PubMed
31.
Zurück zum Zitat 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):e3377PubMed 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):e3377PubMed
32.
Zurück zum Zitat 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):1495–1503PubMed 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):1495–1503PubMed
33.
Zurück zum Zitat 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):700–707PubMed 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):700–707PubMed
34.
Zurück zum Zitat 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):5693–5702PubMed 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):5693–5702PubMed
35.
Zurück zum Zitat 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):323–334PubMed 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):323–334PubMed
36.
Zurück zum Zitat 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):159–166PubMed 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):159–166PubMed
37.
Zurück zum Zitat 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):5790–5798 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):5790–5798
38.
Zurück zum Zitat 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):1360–1371PubMed 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):1360–1371PubMed
39.
Zurück zum Zitat 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):734–738PubMed 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):734–738PubMed
40.
Zurück zum Zitat Salih HR, Rammensee HG, Steinle A (2002) Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding. J Immunol 169(8):4098–4102PubMed Salih HR, Rammensee HG, Steinle A (2002) Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding. J Immunol 169(8):4098–4102PubMed
41.
Zurück zum Zitat 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):5208–5215PubMed 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):5208–5215PubMed
42.
Zurück zum Zitat 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):3571–3578PubMed 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):3571–3578PubMed
43.
Zurück zum Zitat 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):7335–7340PubMed 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):7335–7340PubMed
44.
Zurück zum Zitat 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):4120–4125PubMed 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):4120–4125PubMed
45.
Zurück zum Zitat 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):4118–4125PubMed 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):4118–4125PubMed
46.
Zurück zum Zitat 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):1407–1415PubMed 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):1407–1415PubMed
47.
Zurück zum Zitat 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):5998–6009PubMed 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):5998–6009PubMed
48.
Zurück zum Zitat 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):1826–1834PubMed 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):1826–1834PubMed
49.
Zurück zum Zitat 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):6321–6329PubMed 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):6321–6329PubMed
50.
Zurück zum Zitat 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):2103–2108PubMed 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):2103–2108PubMed
51.
Zurück zum Zitat 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):460–471PubMed 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):460–471PubMed
52.
Zurück zum Zitat 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):806–813PubMed 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):806–813PubMed
53.
Zurück zum Zitat 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):1065–1073PubMed 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):1065–1073PubMed
54.
Zurück zum Zitat 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 Dermatol 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 Dermatol
55.
Zurück zum Zitat 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):1491–1499PubMed 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):1491–1499PubMed
56.
Zurück zum Zitat 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):245–253PubMed 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):245–253PubMed
57.
Zurück zum Zitat 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):2833–2842PubMed 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):2833–2842PubMed
58.
Zurück zum Zitat 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):5545–5550PubMed 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):5545–5550PubMed
59.
Zurück zum Zitat 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):4080–4089PubMed 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):4080–4089PubMed
60.
Zurück zum Zitat 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):258–263PubMed 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):258–263PubMed
61.
Zurück zum Zitat 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):3572–3576PubMed 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):3572–3576PubMed
62.
Zurück zum Zitat 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):95–109PubMed 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):95–109PubMed
63.
Zurück zum Zitat 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):83–90PubMed 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):83–90PubMed
64.
Zurück zum Zitat 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):1260–1265PubMed 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):1260–1265PubMed
65.
Zurück zum Zitat 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):4472–4479PubMed 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):4472–4479PubMed
66.
Zurück zum Zitat 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):1869–1882PubMed 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):1869–1882PubMed
67.
Zurück zum Zitat Maghazachi AA (2010) Role of chemokines in the biology of natural killer cells. Curr Top Microbiol Immunol 341:37–58PubMed Maghazachi AA (2010) Role of chemokines in the biology of natural killer cells. Curr Top Microbiol Immunol 341:37–58PubMed
68.
Zurück zum Zitat 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):79–85PubMed 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):79–85PubMed
69.
Zurück zum Zitat 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):3146–3151PubMed 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):3146–3151PubMed
70.
Zurück zum Zitat 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):6985–6991PubMed 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):6985–6991PubMed
71.
Zurück zum Zitat 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):51–59PubMed 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):51–59PubMed
72.
Zurück zum Zitat 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):417–431PubMed 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):417–431PubMed
73.
Zurück zum Zitat 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):637–660PubMed 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):637–660PubMed
74.
Zurück zum Zitat 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):1599–1608PubMed 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):1599–1608PubMed
75.
Zurück zum Zitat Campoli M, Ferrone S (2008) Tumor escape mechanisms: potential role of soluble HLA antigens and NK cells activating ligands. Tissue Antigens 72(4):321–334PubMed Campoli M, Ferrone S (2008) Tumor escape mechanisms: potential role of soluble HLA antigens and NK cells activating ligands. Tissue Antigens 72(4):321–334PubMed
76.
Zurück zum Zitat 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):413–421PubMed 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):413–421PubMed
77.
Zurück zum Zitat Frey AB, Monu N (2008) Signaling defects in anti-tumor T cells. Immunol Rev 222:192–205PubMed Frey AB, Monu N (2008) Signaling defects in anti-tumor T cells. Immunol Rev 222:192–205PubMed
78.
Zurück zum Zitat Wherry EJ (2011) T cell exhaustion. Nat Immunol 12(6):492–499PubMed Wherry EJ (2011) T cell exhaustion. Nat Immunol 12(6):492–499PubMed
79.
Zurück zum Zitat 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):1537–1544PubMed 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):1537–1544PubMed
80.
Zurück zum Zitat 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):2865–2873PubMed 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):2865–2873PubMed
81.
Zurück zum Zitat 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):5393–5399PubMed 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):5393–5399PubMed
82.
Zurück zum Zitat 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):2286–2294PubMed 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):2286–2294PubMed
83.
Zurück zum Zitat 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):180–205PubMed 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):180–205PubMed
84.
Zurück zum Zitat Miyazaki T, Dierich A, Benoist C, Mathis D (1996) Independent modes of natural killing distinguished in mice lacking Lag3. Science 272(5260):405–408PubMed Miyazaki T, Dierich A, Benoist C, Mathis D (1996) Independent modes of natural killing distinguished in mice lacking Lag3. Science 272(5260):405–408PubMed
85.
Zurück zum Zitat 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):93–96PubMed 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):93–96PubMed
86.
Zurück zum Zitat Cai G, Freeman GJ (2009) The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation. Immunol Rev 229(1):244–258PubMed Cai G, Freeman GJ (2009) The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation. Immunol Rev 229(1):244–258PubMed
87.
Zurück zum Zitat 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):3734–3743PubMed 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):3734–3743PubMed
88.
Zurück zum Zitat 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):3064–3072PubMed 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):3064–3072PubMed
89.
Zurück zum Zitat 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):161–173PubMed 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):161–173PubMed
90.
Zurück zum Zitat 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):276–284PubMed 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):276–284PubMed
91.
Zurück zum Zitat 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 214:219–228PubMed 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 214:219–228PubMed
92.
Zurück zum Zitat 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):1417–1426 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):1417–1426
93.
Zurück zum Zitat 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):289–293 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):289–293
94.
Zurück zum Zitat Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174PubMed Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174PubMed
95.
Zurück zum Zitat 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):240–249PubMed 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):240–249PubMed
96.
Zurück zum Zitat 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):1582–1587PubMed 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):1582–1587PubMed
97.
Zurück zum Zitat 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):1075–1085PubMed 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):1075–1085PubMed
98.
Zurück zum Zitat 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):554–567PubMed 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):554–567PubMed
99.
Zurück zum Zitat 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):2343–2353PubMed 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):2343–2353PubMed
100.
Zurück zum Zitat 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):718–725PubMed 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):718–725PubMed
101.
Zurück zum Zitat 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):704–713PubMed 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):704–713PubMed
102.
Zurück zum Zitat 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):4513–4519PubMed 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):4513–4519PubMed
103.
Zurück zum Zitat 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):8437–8445PubMed 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):8437–8445PubMed
104.
Zurück zum Zitat 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):3853–3864PubMed 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):3853–3864PubMed
105.
Zurück zum Zitat 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):3865–3874PubMed 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):3865–3874PubMed
106.
Zurück zum Zitat 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):577–583PubMed 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):577–583PubMed
107.
Zurück zum Zitat 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):23–28PubMed 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):23–28PubMed
108.
Zurück zum Zitat 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):905–912PubMed 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):905–912PubMed
109.
Zurück zum Zitat 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):32–40PubMed 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):32–40PubMed
110.
Zurück zum Zitat 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):541–546PubMed 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):541–546PubMed
111.
Zurück zum Zitat 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):603–609PubMed 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):603–609PubMed
112.
Zurück zum Zitat Hayakawa Y, Huntington ND, Nutt SL, Smyth MJ (2006) Functional subsets of mouse natural killer cells. Immunol Rev 214:47–55PubMed Hayakawa Y, Huntington ND, Nutt SL, Smyth MJ (2006) Functional subsets of mouse natural killer cells. Immunol Rev 214:47–55PubMed
113.
Zurück zum Zitat 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):7468–7474PubMed 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):7468–7474PubMed
114.
Zurück zum Zitat 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):1427–1435PubMed 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):1427–1435PubMed
115.
Zurück zum Zitat Blobel CP (2005) ADAMs: key components in EGFR signalling and development. Nat Rev Mol Cell Biol 6(1):32–43PubMed Blobel CP (2005) ADAMs: key components in EGFR signalling and development. Nat Rev Mol Cell Biol 6(1):32–43PubMed
116.
Zurück zum Zitat 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):985–1006PubMed 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):985–1006PubMed
117.
Zurück zum Zitat White JM (2003) ADAMs: modulators of cell-cell and cell-matrix interactions. Curr Opin Cell Biol 15(5):598–606PubMed White JM (2003) ADAMs: modulators of cell-cell and cell-matrix interactions. Curr Opin Cell Biol 15(5):598–606PubMed
118.
Zurück zum Zitat 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):6368–6376PubMed 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):6368–6376PubMed
119.
Zurück zum Zitat 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):49–53PubMed 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):49–53PubMed
120.
Zurück zum Zitat 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 359PubMed 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 359PubMed
121.
Zurück zum Zitat 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):1795–1799PubMed 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):1795–1799PubMed
Metadaten
Titel
Shaping of NK Cell Responses by the Tumor Microenvironment
verfasst von
Ana Stojanovic
Margareta P. Correia
Adelheid Cerwenka
Publikationsdatum
01.08.2013
Verlag
Springer Netherlands
Erschienen in
Cancer Microenvironment / Ausgabe 2/2013
Print ISSN: 1875-2292
Elektronische ISSN: 1875-2284
DOI
https://doi.org/10.1007/s12307-012-0125-8

Weitere Artikel der Ausgabe 2/2013

Cancer Microenvironment 2/2013 Zur Ausgabe

Adjuvante Immuntherapie verlängert Leben bei RCC

25.04.2024 Nierenkarzinom Nachrichten

Nun gibt es auch Resultate zum Gesamtüberleben: Eine adjuvante Pembrolizumab-Therapie konnte in einer Phase-3-Studie das Leben von Menschen mit Nierenzellkarzinom deutlich verlängern. Die Sterberate war im Vergleich zu Placebo um 38% geringer.

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

25.04.2024 NSCLC Nachrichten

Das Risiko für Rezidiv oder Tod von Patienten und Patientinnen mit reseziertem ALK-positivem NSCLC ist unter einer adjuvanten Therapie mit dem Tyrosinkinase-Inhibitor Alectinib signifikant geringer als unter platinbasierter Chemotherapie.

Bei Senioren mit Prostatakarzinom auf Anämie achten!

24.04.2024 DGIM 2024 Nachrichten

Patienten, die zur Behandlung ihres Prostatakarzinoms eine Androgendeprivationstherapie erhalten, entwickeln nicht selten eine Anämie. Wer ältere Patienten internistisch mitbetreut, sollte auf diese Nebenwirkung achten.

ICI-Therapie in der Schwangerschaft wird gut toleriert

Müssen sich Schwangere einer Krebstherapie unterziehen, rufen Immuncheckpointinhibitoren offenbar nicht mehr unerwünschte Wirkungen hervor als andere Mittel gegen Krebs.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.