Semin Liver Dis 2017; 37(03): 198-209
DOI: 10.1055/s-0037-1603946
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Natural Killer Cells in Liver Disease

Victoria Male
1   Division of Infection and Immunity, University College London, Institute of Immunity and Transplantation, UCL Medical School, London, United Kingdom
,
Kerstin A. Stegmann
2   Division of Infection and Immunity, University College London, London, United Kingdom
,
Nicholas J. Easom
2   Division of Infection and Immunity, University College London, London, United Kingdom
,
Mala K. Maini
2   Division of Infection and Immunity, University College London, London, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
28 August 2017 (online)

Abstract

Natural killer (NK) cells comprise one of the most abundant immune cell populations in human liver and the nature and functions of these cells have been a focus of recent interest. Here, we consider the possible roles of NK cells in diverse liver diseases, concentrating on data from patient studies. NK cells can be protective, killing virally infected and cancerous cells in the liver and limiting fibrosis by eliminating hepatic stellate cells. However, they can also be deleterious, contributing to pathology in viral hepatitis by killing hepatocytes and downregulating virus-specific T-cell responses. It has recently emerged that a large fraction of hepatic NK cells constitute a distinct liver-resident subset and we highlight the need to distinguish between circulating and liver-resident NK cells in future studies. There is also a need for further investigation into how NK cells are influenced by the liver microenvironment and what scope there is to harness their immunotherapeutic potential.

 
  • References

  • 1 Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol 2008; 9 (05) 503-510
  • 2 Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 2008; 9 (05) 495-502
  • 3 Vivier E, Raulet DH, Moretta A. , et al. Innate or adaptive immunity? The example of natural killer cells. Science 2011; 331 (6013): 44-49
  • 4 Sojka DK, Tian Z, Yokoyama WM. Tissue-resident natural killer cells and their potential diversity. Semin Immunol 2014; 26 (02) 127-131
  • 5 Melsen JE, Lugthart G, Lankester AC, Schilham MW. Human circulating and tissue-resident CD56(bright) natural killer cell populations. Front Immunol 2016; 7: 262
  • 6 Doherty DG, Norris S, Madrigal-Estebas L. , et al. The human liver contains multiple populations of NK cells, T cells, and CD3+CD56+ natural T cells with distinct cytotoxic activities and Th1, Th2, and Th0 cytokine secretion patterns. J Immunol 1999; 163 (04) 2314-2321
  • 7 Ishiyama K, Ohdan H, Ohira M, Mitsuta H, Arihiro K, Asahara T. Difference in cytotoxicity against hepatocellular carcinoma between liver and periphery natural killer cells in humans. Hepatology 2006; 43 (02) 362-372
  • 8 Burt BM, Plitas G, Zhao Z. , et al. The lytic potential of human liver NK cells is restricted by their limited expression of inhibitory killer Ig-like receptors. J Immunol 2009; 183 (03) 1789-1796
  • 9 Guidotti LG, Inverso D, Sironi L. , et al. Immunosurveillance of the liver by intravascular effector CD8(+) T cells. Cell 2015; 161 (03) 486-500
  • 10 Wisse E, van't Noordende JM, van der Meulen J, Daems WT. The pit cell: description of a new type of cell occurring in rat liver sinusoids and peripheral blood. Cell Tissue Res 1976; 173 (04) 423-435
  • 11 Tu Z, Bozorgzadeh A, Pierce RH, Kurtis J, Crispe IN, Orloff MS. TLR-dependent cross talk between human Kupffer cells and NK cells. J Exp Med 2008; 205 (01) 233-244
  • 12 Gordon SM, Chaix J, Rupp LJ. , et al. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity 2012; 36 (01) 55-67
  • 13 Daussy C, Faure F, Mayol K. , et al. T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow. J Exp Med 2014; 211 (03) 563-577
  • 14 Sojka DK, Plougastel-Douglas B, Yang L. , et al. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. eLife 2014; 3: e01659
  • 15 Marquardt N, Béziat V, Nyström S. , et al. Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells. J Immunol 2015; 194 (06) 2467-2471
  • 16 Male V. Liver-resident NK cells: the human factor. Trends Immunol 2017; 38 (05) 307-309
  • 17 Hudspeth K, Donadon M, Cimino M. , et al. Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways. J Autoimmun 2016; 66: 40-50
  • 18 Stegmann KA, Robertson F, Hansi N. , et al. CXCR6 marks a novel subset of T-bet(lo)Eomes(hi) natural killer cells residing in human liver. Sci Rep 2016; 6: 26157
  • 19 Cuff AO, Robertson FP, Stegmann KA. , et al. Eomeshi NK cells in human liver are long-lived and do not recirculate but can be replenished from the circulation. J Immunol 2016; 197 (11) 4283-4291
  • 20 Harmon C, Robinson MW, Fahey R. , et al. Tissue-resident Eomes(hi) T-bet(lo) CD56(bright) NK cells with reduced proinflammatory potential are enriched in the adult human liver. Eur J Immunol 2016; 46 (09) 2111-2120
  • 21 Paust S, Gill HS, Wang BZ. , et al. Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nat Immunol 2010; 11 (12) 1127-1135
  • 22 Peng H, Jiang X, Chen Y. , et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest 2013; 123 (04) 1444-1456
  • 23 Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 2006; 130 (02) 435-452
  • 24 Radaeva S, Wang L, Radaev S, Jeong WI, Park O, Gao B. Retinoic acid signaling sensitizes hepatic stellate cells to NK cell killing via upregulation of NK cell activating ligand RAE1. Am J Physiol Gastrointest Liver Physiol 2007; 293 (04) G809-G816
  • 25 Krizhanovsky V, Yon M, Dickins RA. , et al. Senescence of activated stellate cells limits liver fibrosis. Cell 2008; 134 (04) 657-667
  • 26 Gur C, Doron S, Kfir-Erenfeld S. , et al. NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis. Gut 2012; 61 (06) 885-893
  • 27 Melhem A, Muhanna N, Bishara A. , et al. Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J Hepatol 2006; 45 (01) 60-71
  • 28 Muhanna N, Abu Tair L, Doron S. , et al. Amelioration of hepatic fibrosis by NK cell activation. Gut 2011; 60 (01) 90-98
  • 29 Glässner A, Eisenhardt M, Krämer B. , et al. NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner. Lab Invest 2012; 92 (07) 967-977
  • 30 Morishima C, Paschal DM, Wang CC. , et al. Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. Hepatology 2006; 43 (03) 573-580
  • 31 Berglin L, Bergquist A, Johansson H. , et al. In situ characterization of intrahepatic non-parenchymal cells in PSC reveals phenotypic patterns associated with disease severity. PLoS One 2014; 9 (08) e105375
  • 32 Park SH, Rehermann B. Immune responses to HCV and other hepatitis viruses. Immunity 2014; 40 (01) 13-24
  • 33 Webster GJ, Reignat S, Maini MK. , et al. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology 2000; 32 (05) 1117-1124
  • 34 Fisicaro P, Valdatta C, Boni C. , et al. Early kinetics of innate and adaptive immune responses during hepatitis B virus infection. Gut 2009; 58 (07) 974-982
  • 35 Dunn C, Peppa D, Khanna P. , et al. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology 2009; 137 (04) 1289-1300
  • 36 Bertoletti A, Maini MK, Ferrari C. The host-pathogen interaction during HBV infection: immunological controversies. Antivir Ther 2010; 15 (Suppl. 03) 15-24
  • 37 Rehermann B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat Med 2013; 19 (07) 859-868
  • 38 Bertoletti A, Kennedy PT. The immune tolerant phase of chronic HBV infection: new perspectives on an old concept. Cell Mol Immunol 2015; 12 (03) 258-263
  • 39 Sprengers D, van der Molen RG, Kusters JG. , et al. Different composition of intrahepatic lymphocytes in the immune-tolerance and immune-clearance phase of chronic hepatitis B. J Med Virol 2006; 78 (05) 561-568
  • 40 Zhang Z, Zhang S, Zou Z. , et al. Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients. Hepatology 2011; 53 (01) 73-85
  • 41 Nattermann J, Feldmann G, Ahlenstiel G, Langhans B, Sauerbruch T, Spengler U. Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut 2006; 55 (06) 869-877
  • 42 Li Y, Wang JJ, Gao S. , et al. Decreased peripheral natural killer cells activity in the immune activated stage of chronic hepatitis B. PLoS One 2014; 9 (02) e86927
  • 43 Oliviero B, Varchetta S, Paudice E. , et al. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 2009; 137 (03) 1151-1160 , 1160.e1–1160.e7
  • 44 Tjwa ETTL, van Oord GW, Hegmans JP, Janssen HLA, Woltman AM. Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. J Hepatol 2011; 54 (02) 209-218
  • 45 Li F, Wei H, Wei H. , et al. Blocking the natural killer cell inhibitory receptor NKG2A increases activity of human natural killer cells and clears hepatitis B virus infection in mice. Gastroenterology 2013; 144 (02) 392-401
  • 46 Peppa D, Micco L, Javaid A. , et al. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection. PLoS Pathog 2010; 6 (12) e1001227-e10
  • 47 Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 2006; 1: 23-61
  • 48 Sun C, Fu B, Gao Y. , et al. TGF-β1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence. PLoS Pathog 2012; 8 (03) e1002594
  • 49 Shi CC, Tjwa ET, Biesta PJ. , et al. Hepatitis B virus suppresses the functional interaction between natural killer cells and plasmacytoid dendritic cells. J Viral Hepat 2012; 19 (02) e26-e33
  • 50 Dunn C, Brunetto M, Reynolds G. , et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med 2007; 204 (03) 667-680
  • 51 Maini MK, Peppa D. NK cells: a double-edged sword in chronic hepatitis B virus infection. Front Immunol 2013; 4: 57
  • 52 Peppa D, Gill US, Reynolds G. , et al. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp Med 2013; 210 (01) 99-114
  • 53 Crome SQ, Lang PA, Lang KS, Ohashi PS. Natural killer cells regulate diverse T cell responses. Trends Immunol 2013; 34 (07) 342-349
  • 54 Waggoner SN, Reighard SD, Gyurova IE. , et al. Roles of natural killer cells in antiviral immunity. Curr Opin Virol 2016; 16: 15-23
  • 55 Huang WC, Easom NJ, Tang XZ. , et al. T cells infiltrating diseased liver express ligands for the NKG2D stress surveillance system. J Immunol 2017; 198 (03) 1172-1182
  • 56 Boni C, Lampertico P, Talamona L. , et al. Natural killer cell phenotype modulation and natural killer/T-cell interplay in nucleos(t)ide analogue-treated hepatitis e antigen-negative patients with chronic hepatitis B. Hepatology 2015; 62 (06) 1697-1709
  • 57 Micco L, Peppa D, Loggi E. , et al. Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B. J Hepatol 2013; 58 (02) 225-233
  • 58 Gill US, Peppa D, Micco L. , et al. Interferon alpha induces sustained changes in NK cell responsiveness to hepatitis B viral load suppression in vivo. PLoS Pathog 2016; 12 (08) e1005788
  • 59 Khakoo SI, Thio CL, Martin MP. , et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 2004; 305 (5685): 872-874
  • 60 Knapp S, Warshow U, Ho KM. , et al. A polymorphism in IL28B distinguishes exposed, uninfected individuals from spontaneous resolvers of HCV infection. Gastroenterology 2011; 141 (01) 320-325 , 325.e1–325.e2
  • 61 Golden-Mason L, Cox AL, Randall JA, Cheng L, Rosen HR. Increased natural killer cell cytotoxicity and NKp30 expression protects against hepatitis C virus infection in high-risk individuals and inhibits replication in vitro. Hepatology 2010; 52 (05) 1581-1589
  • 62 Sugden PB, Cameron B, Mina M, Lloyd AR. ; HITS investigators. Protection against hepatitis C infection via NK cells in highly-exposed uninfected injecting drug users. J Hepatol 2014; 61 (04) 738-745
  • 63 Werner JM, Heller T, Gordon AM. , et al. Innate immune responses in hepatitis C virus-exposed healthcare workers who do not develop acute infection. Hepatology 2013; 58 (05) 1621-1631
  • 64 Ahlenstiel G, Titerence RH, Koh C. , et al. Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner. Gastroenterology 2010; 138 (01) 325-35.e1 , 2
  • 65 Stegmann KA, Björkström NK, Veber H. , et al. Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection. Gastroenterology 2010; 138 (05) 1885-1897
  • 66 Oliviero B, Mele D, Degasperi E. , et al. Natural killer cell dynamic profile is associated with treatment outcome in patients with chronic HCV infection. J Hepatol 2013; 59 (01) 38-44
  • 67 Golden-Mason L, Bambha KM, Cheng L. , et al; Virahep-C Study Group. Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C. Hepatology 2011; 54 (05) 1559-1569
  • 68 Ahlenstiel G, Edlich B, Hogdal LJ. , et al. Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C. Gastroenterology 2011; 141 (04) 1231-1239 , 1239.e1–1239.e2
  • 69 Bonorino P, Ramzan M, Camous X. , et al. Fine characterization of intrahepatic NK cells expressing natural killer receptors in chronic hepatitis B and C. J Hepatol 2009; 51 (03) 458-467
  • 70 De Maria A, Fogli M, Mazza S. , et al. Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients. Eur J Immunol 2007; 37 (02) 445-455
  • 71 Varchetta S, Mele D, Mantovani S. , et al. Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection. Hepatology 2012; 56 (03) 841-849
  • 72 Krämer B, Körner C, Kebschull M. , et al. Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis. Hepatology 2012; 56 (04) 1201-1213
  • 73 Edlich B, Ahlenstiel G, Zabaleta Azpiroz A. , et al. Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C patients. Hepatology 2012; 55 (01) 39-48
  • 74 Stegmann KA, Björkström NK, Ciesek S. , et al. Interferon α-stimulated natural killer cells from patients with acute hepatitis C virus (HCV) infection recognize HCV-infected and uninfected hepatoma cells via DNAX accessory molecule-1. J Infect Dis 2012; 205 (09) 1351-1362
  • 75 Kurane I, Binn LN, Bancroft WH, Ennis FA. Human lymphocyte responses to hepatitis A virus-infected cells: interferon production and lysis of infected cells. J Immunol 1985; 135 (03) 2140-2144
  • 76 Baba M, Hasegawa H, Nakayabu M, Fukai K, Suzuki S. Cytolytic activity of natural killer cells and lymphokine activated killer cells against hepatitis A virus infected fibroblasts. J Clin Lab Immunol 1993; 40 (02) 47-60
  • 77 Müller C, Gödl I, Göttlicher J, Wolf HM, Eibel MM. Phenotypes of peripheral blood lymphocytes during acute hepatitis A. Acta Paediatr Scand 1991; 80 (10) 931-937
  • 78 Cho H. Phenotypic characteristics of natural killer cells in acute hepatitis. J Microbiol 2013; 51 (02) 247-251
  • 79 Das R, Tripathy A. Increased expressions of NKp44, NKp46 on NK/NKT-like cells are associated with impaired cytolytic function in self-limiting hepatitis E infection. Med Microbiol Immunol (Berl) 2014; 203 (05) 303-314
  • 80 Srivastava R, Aggarwal R, Bhagat MR, Chowdhury A, Naik S. Alterations in natural killer cells and natural killer T cells during acute viral hepatitis E. J Viral Hepat 2008; 15 (12) 910-916
  • 81 Jeong WI, Park O, Gao B. Abrogation of the antifibrotic effects of natural killer cells/interferon-gamma contributes to alcohol acceleration of liver fibrosis. Gastroenterology 2008; 134 (01) 248-258
  • 82 Zhang F, Little A, Zhang H. Chronic alcohol consumption inhibits peripheral NK cell development and maturation by decreasing the availability of IL-15. J Leukoc Biol 2017; 101 (04) 1015-1027
  • 83 Laso FJ, Almeida J, Torres E, Vaquero JM, Marcos M, Orfao A. Chronic alcohol consumption is associated with an increased cytotoxic profile of circulating lymphocytes that may be related with the development of liver injury. Alcohol Clin Exp Res 2010; 34 (05) 876-885
  • 84 O'Rourke RW, Meyer KA, Neeley CK. , et al. Systemic NK cell ablation attenuates intra-abdominal adipose tissue macrophage infiltration in murine obesity. Obesity (Silver Spring) 2014; 22 (10) 2109-2114
  • 85 Wensveen FM, Jelenčić V, Valentić S. , et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat Immunol 2015; 16 (04) 376-385
  • 86 Lee BC, Kim MS, Pae M. , et al. Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity. Cell Metab 2016; 23 (04) 685-698
  • 87 O'Shea D, Cawood TJ, O'Farrelly C, Lynch L. Natural killer cells in obesity: impaired function and increased susceptibility to the effects of cigarette smoke. PLoS One 2010; 5 (01) e8660
  • 88 Kahraman A, Schlattjan M, Kocabayoglu P. , et al. Major histocompatibility complex class I-related chains A and B (MIC A/B): a novel role in nonalcoholic steatohepatitis. Hepatology 2010; 51 (01) 92-102
  • 89 Tosello-Trampont AC, Krueger P, Narayanan S, Landes SG, Leitinger N, Hahn YS. NKp46(+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice. Hepatology 2016; 63 (03) 799-812
  • 90 Kaneda K, Kurioka N, Seki S, Wake K, Yamamoto S. Pit cell-hepatocyte contact in autoimmune hepatitis. Hepatology 1984; 4 (05) 955-958
  • 91 Donaldson PT, Doherty DG, Hayllar KM, McFarlane IG, Johnson PJ, Williams R. Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors. Hepatology 1991; 13 (04) 701-706
  • 92 Muratori P, Czaja A-J, Muratori L. , et al. Genetic distinctions between autoimmune hepatitis in Italy and North America. World J Gastroenterol 2005; 11 (12) 1862-1866
  • 93 Littera R, Chessa L, Onali S. , et al. Exploring the role of killer cell immunoglobulin-like receptors and their HLA Class I ligands in autoimmune hepatitis. PLoS One 2016; 11 (01) e0146086-e14
  • 94 Chuang Y-H, Lian Z-X, Tsuneyama K. , et al. Increased killing activity and decreased cytokine production in NK cells in patients with primary biliary cirrhosis. J Autoimmun 2006; 26 (04) 232-240
  • 95 Chuang Y-H, Lian Z-X, Cheng C-M. , et al. Increased levels of chemokine receptor CXCR3 and chemokines IP-10 and MIG in patients with primary biliary cirrhosis and their first degree relatives. J Autoimmun 2005; 25 (02) 126-132
  • 96 Isse K, Harada K, Zen Y. , et al. Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts. Hepatology 2005; 41 (03) 506-516
  • 97 Shimoda S, Harada K, Niiro H. , et al. Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis. Hepatology 2011; 53 (04) 1270-1281
  • 98 Shimoda S, Hisamoto S, Harada K. , et al. Natural killer cells regulate T cell immune responses in primary biliary cirrhosis. Hepatology 2015; 62 (06) 1817-1827
  • 99 Hata K, Zhang XR, Iwatsuki S, Van Thiel DH, Herberman RB, Whiteside TL. Isolation, phenotyping, and functional analysis of lymphocytes from human liver. Clin Immunol Immunopathol 1990; 56 (03) 401-419
  • 100 Bo X, Broome U, Remberger M, Sumitran-Holgersson S. Tumour necrosis factor alpha impairs function of liver derived T lymphocytes and natural killer cells in patients with primary sclerosing cholangitis. Gut 2001; 49 (01) 131-141
  • 101 Norris S, Kondeatis E, Collins R. , et al. Mapping MHC-encoded susceptibility and resistance in primary sclerosing cholangitis: the role of MICA polymorphism. Gastroenterology 2001; 120 (06) 1475-1482
  • 102 Wiencke K, Spurkland A, Schrumpf E, Boberg KM. Primary sclerosing cholangitis is associated to an extended B8-DR3 haplotype including particular MICA and MICB alleles. Hepatology 2001; 34 (4 Pt 1): 625-630
  • 103 Karlsen TH, Boberg KM, Olsson M. , et al. Particular genetic variants of ligands for natural killer cell receptors may contribute to the HLA associated risk of primary sclerosing cholangitis. J Hepatol 2007; 46 (05) 899-906
  • 104 Melum E, Karlsen TH, Schrumpf E. , et al. Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms. Hepatology 2008; 47 (01) 90-96
  • 105 Huang J, Xu L, Luo Y, He F, Zhang Y, Chen M. The inflammation-based scores to predict prognosis of patients with hepatocellular carcinoma after hepatectomy. Med Oncol 2014; 31 (04) 883-888
  • 106 Cai L, Zhang Z, Zhou L. , et al. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin Immunol 2008; 129 (03) 428-437
  • 107 Guillerey C, Huntington ND, Smyth MJ. Targeting natural killer cells in cancer immunotherapy. Nat Immunol 2016; 17 (09) 1025-1036
  • 108 Kamimura H, Yamagiwa S, Tsuchiya A. , et al. Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence. J Hepatol 2012; 56 (02) 381-388
  • 109 Fang L, Gong J, Wang Y. , et al. MICA/B expression is inhibited by unfolded protein response and associated with poor prognosis in human hepatocellular carcinoma. J Exp Clin Cancer Res 2014; 33: 76
  • 110 Kumar V, Kato N, Urabe Y. , et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet 2011; 43 (05) 455-458
  • 111 Kumar V, Yi Lo PH, Sawai H. , et al. Soluble MICA and a MICA variation as possible prognostic biomarkers for HBV-induced hepatocellular carcinoma. PLoS One 2012; 7 (09) e44743
  • 112 Tong HV, Toan NL, Song LH, Bock CT, Kremsner PG, Velavan TP. Hepatitis B virus-induced hepatocellular carcinoma: functional roles of MICA variants. J Viral Hepat 2013; 20 (10) 687-698
  • 113 Pan N, Jiang W, Sun H. , et al. KIR and HLA loci are associated with hepatocellular carcinoma development in patients with hepatitis B virus infection: a case-control study. PLoS One 2011; 6 (10) e25682
  • 114 Sheppard S, Guedes J, Mroz A. , et al. The immunoreceptor NKG2D promotes tumour growth in a model of hepatocellular carcinoma. Nat Commun 2017; 8: 13930
  • 115 Kamiya T, Chang YH, Campana D. Expanded and activated natural killer cells for immunotherapy of hepatocellular carcinoma. Cancer Immunol Res 2016; 4 (07) 574-581
  • 116 Wongkajornsilp A, Somchitprasert T, Butraporn R. , et al. Human cytokine-induced killer cells specifically infiltrated and retarded the growth of the inoculated human cholangiocarcinoma cells in SCID mice. Cancer Invest 2009; 27 (02) 140-148
  • 117 Ahn E-Y, Pan G, Vickers SM, McDonald JM. IFN-gamma upregulates apoptosis-related molecules and enhances Fas-mediated apoptosis in human cholangiocarcinoma. Int J Cancer 2002; 100 (04) 445-451
  • 118 Takeda K, Smyth MJ, Cretney E. , et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in NK cell-mediated and IFN-γ-dependent suppression of subcutaneous tumor growth. Cell Immunol 2001; 214 (02) 194-200
  • 119 Smyth MJ, Crowe NY, Godfrey DI. NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int Immunol 2001; 13 (04) 459-463
  • 120 Pugh SA, Harrison RJ, Primrose JN, Khakoo SI. T cells but not NK cells are associated with a favourable outcome for resected colorectal liver metastases. BMC Cancer 2014; 14: 180
  • 121 Galon J, Costes A, Sanchez-Cabo F. , et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006; 313 (5795): 1960-1964
  • 122 Halama N, Michel S, Kloor M. , et al. Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res 2011; 71 (17) 5670-5677
  • 123 Floros T, Tarhini AA. Anticancer cytokines: biology and clinical effects of interferon-α2, interleukin (IL)-2, IL-15, IL-21, and IL-12. Semin Oncol 2015; 42 (04) 539-548
  • 124 Parihar R, Nadella P, Lewis A. , et al. A phase I study of interleukin 12 with trastuzumab in patients with human epidermal growth factor receptor-2-overexpressing malignancies: analysis of sustained interferon gamma production in a subset of patients. Clin Cancer Res 2004; 10 (15) 5027-5037
  • 125 Lagrue K, Carisey A, Morgan DJ, Chopra R, Davis DM. Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds. Blood 2015; 126 (01) 50-60
  • 126 Fowler NH, Davis RE, Rawal S. , et al. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol 2014; 15 (12) 1311-1318
  • 127 Lappas CM, Day YJ, Marshall MA, Engelhard VH, Linden J. Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation. J Exp Med 2006; 203 (12) 2639-2648
  • 128 Beldi G, Banz Y, Kroemer A. , et al. Deletion of CD39 on natural killer cells attenuates hepatic ischemia/reperfusion injury in mice. Hepatology 2010; 51 (05) 1702-1711
  • 129 Kroemer A, Xiao X, Degauque N. , et al. The innate NK cells, allograft rejection, and a key role for IL-15. J Immunol 2008; 180 (12) 7818-7826
  • 130 Obara H, Nagasaki K, Hsieh CL. , et al. IFN-gamma, produced by NK cells that infiltrate liver allografts early after transplantation, links the innate and adaptive immune responses. Am J Transplant 2005; 5 (09) 2094-2103
  • 131 Moya-Quiles MR, Torío A, Muro M. , et al. Impact of HLA-C on acute rejection in liver transplantation. Transplant Proc 2003; 35 (05) 1892-1893
  • 132 Hanvesakul R, Spencer N, Cook M. , et al. Donor HLA-C genotype has a profound impact on the clinical outcome following liver transplantation. Am J Transplant 2008; 8 (09) 1931-1941
  • 133 Moroso V, van der Meer A, Tilanus HW. , et al. Donor and recipient HLA/KIR genotypes do not predict liver transplantation outcome. Transpl Int 2011; 24 (09) 932-942
  • 134 Pembroke T, Gallimore A, Godkin A. Tracking the kinetics of intrahepatic immune responses by repeated fine needle aspiration of the liver. J Immunol Methods 2015; 424: 131-135
  • 135 Cerwenka A, Lanier LL. Natural killer cell memory in infection, inflammation and cancer. Nat Rev Immunol 2016; 16 (02) 112-123
  • 136 Lunemann S, Martrus G, Hölzemer A. , et al. Sequence variations in HCV core-derived epitopes alter binding of KIR2DL3 to HLA-Co*03:04 and modulate NK cell function. J Hepatol 2016; 65 (02) 252-258
  • 137 Cassidy SA, Cheent KS, Khakoo SI. Effects of peptide on NK cell-mediated MHC I recognition. Front Immunol 2014; 5: 133
  • 138 Mazza G, Rombouts K, Rennie Hall A. , et al. Decellularized human liver as a natural 3D-scaffold for liver bioengineering and transplantation. Sci Rep 2015; 5: 13079
  • 139 Balsamo M, Manzini C, Pietra G. , et al. Hypoxia downregulates the expression of activating receptors involved in NK-cell-mediated target cell killing without affecting ADCC. Eur J Immunol 2013; 43 (10) 2756-2764
  • 140 Gardiner CM, Finlay DK. What fuels natural killers? Metabolism and NK cell responses. Front Immunol 2017; 8: 367
  • 141 Viel S, Marçais A, Guimaraes FS. , et al. TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci Signal 2016; 9 (415) ra19
  • 142 Keating SE, Zaiatz-Bittencourt V, Loftus RM. , et al. Metabolic reprogramming supports IFN-γ production by CD56bright NK cells. J Immunol 2016; 196 (06) 2552-2560
  • 143 Wolter F, Glässner A, Krämer B. , et al. Hypoxia impairs anti-viral activity of natural killer (NK) cells but has little effect on anti-fibrotic NK cell functions in hepatitis C virus infection. J Hepatol 2015; 63 (06) 1334-1344
  • 144 Velásquez SY, Killian D, Schulte J, Sticht C, Thiel M, Lindner HA. Short term hypoxia synergizes with interleukin 15 priming in driving glycolytic gene transcription and supports human natural killer cell activities. J Biol Chem 2016; 291 (25) 12960-12977