Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

Cellular & Molecular Immunology volume 12, pages 292–302 (2015)Cite this article

Abstract

Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation between chronic hepatitis B virus (HBV) infection and hepatocarcinogenesis. As the first line of host defense against viral infections and tumors, natural killer (NK) cells express a large number of immune recognition receptors (NK receptors (NKRs)) to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. Unfortunately, the percentage and absolute number of liver NK cells decrease significantly during the development and progression of HCC. The abnormal expression of NK cell receptors and dysfunction of liver NK cells contribute to the progression of chronic HBV infection and HCC and are significantly associated with poor prognosis for liver cancer. In this review, we focus on the role of NK cell receptors in anti-tumor immune responses in HCC, particularly HBV-related HCC. We discuss specifically how tumor cells evade attack from NK cells and how emerging understanding of NKRs may aid the development of novel treatments for HCC. Novel mono- and combination therapeutic strategies that target the NK cell receptor–ligand system may potentially lead to successful and effective immunotherapy in HCC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. El-Serag HB . Hepatocellular carcinoma. N Engl J Med 2011; 365: 1118–1127.

    CAS  PubMed  Google Scholar 

  2. El-Serag HB, Rudolph KL . Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132: 2557–2576.

    CAS  PubMed  Google Scholar 

  3. Ferenci P, Fried M, Labrecque D, Bruix J, Sherman M, Omata M et al. Hepatocellular carcinoma (HCC): a global perspective. J Clin Gastroenterol 2010; 44: 239–245.

    PubMed  Google Scholar 

  4. El-Serag HB . Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012; 142: 1264–1273.

    PubMed  Google Scholar 

  5. Ferenci P, Fried M, Labrecque D, Bruix J, Sherman M, Omata M et al. World Gastroenterology Organisation Guideline. Hepatocellular carcinoma (HCC): a global perspective. J Gastrointestin Liver Dis 2010; 19: 311–317.

    PubMed  Google Scholar 

  6. Welzel TM, Graubard BI, Quraishi S, Zeuzem S, Davila JA, El-Serag HB et al. Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. Am J Gastroenterol 2013; 108: 1314–1321.

    PubMed  PubMed Central  Google Scholar 

  7. Harkisoen S, Arends JE, van Erpecum KJ, van den Hoek A, Hoepelman AI . Hepatitis B viral load and risk of HBV-related liver disease: from East to West? Ann Hepatol 2012; 11: 164–171.

    PubMed  Google Scholar 

  8. Chew V, Chen J, Lee D, Loh E, Lee J, Lim KH et al. Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma. Gut 2012; 61: 427–438.

    CAS  PubMed  Google Scholar 

  9. Gajewski TF, Schreiber H, Fu YX . Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 2013; 14: 1014–1022.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Fu YX . New immune therapy targets tumor-associated environment: from bone marrow to tumor site. Cell Mol Immunol 2012; 9: 1–2.

    PubMed  Google Scholar 

  11. Wang H, Chen L . Tumor microenviroment and hepatocellular carcinoma metastasis. J Gastroenterol Hepatol 2013; 28( Suppl 1): 43–48.

    PubMed  Google Scholar 

  12. Gao B, Jeong WI, Tian Z . Liver: an organ with predominant innate immunity. Hepatology 2008; 47: 729–736.

    CAS  PubMed  Google Scholar 

  13. Sun H, Sun C, Tian Z, Xiao W . NK cells in immunotolerant organs. Cell Mol Immunol 2013; 10: 202–212.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Li F, Tian Z . The liver works as a school to educate regulatory immune cells. Cell Mol Immunol 2013; 10: 292–302.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Peng H, Jiang X, Chen Y, Sojka DK, Wei H, Gao X et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest 2013; 123: 1444–1456.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Jiang X, Chen Y, Peng H, Tian Z . Memory NK cells: why do they reside in the liver? Cell Mol Immunol 2013; 10: 196–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 2009; 50: 799–807.

    CAS  PubMed  Google Scholar 

  18. Koch J, Steinle A, Watzl C, Mandelboim O . Activating natural cytotoxicity receptors of natural killer cells in cancer and infection. Trends Immunol 2013; 34: 182–191.

    CAS  PubMed  Google Scholar 

  19. Sabry M, Lowdell MW . Tumor-primed NK cells: waiting for the green light. Front Immunol 2013; 4: 408.

    PubMed  PubMed Central  Google Scholar 

  20. Fiegler N, Textor S, Arnold A, Rolle A, Oehme I, Breuhahn K et al. Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells. Blood 2013; 122: 684–693.

    CAS  PubMed  Google Scholar 

  21. Tallerico R, Todaro M, Di Franco S, Maccalli C, Garofalo C, Sottile R et al. Human NK cells selective targeting of colon cancer-initiating cells: a role for natural cytotoxicity receptors and MHC class I molecules. J Immunol 2013; 190: 2381–2390.

    CAS  PubMed  Google Scholar 

  22. Chinnery F, King CA, Elliott T, Bateman AR, James E . Viral antigen mediated NKp46 activation of NK cells results in tumor rejection via NK–DC crosstalk. Oncoimmunology 2012; 1: 874–883.

    PubMed  PubMed Central  Google Scholar 

  23. Thielens A, Vivier E, Romagne F . NK cell MHC class I specific receptors (KIR): from biology to clinical intervention. Curr Opin Immunol 2012; 24: 239–245.

    CAS  PubMed  Google Scholar 

  24. Malhotra A, Shanker A . NK cells: immune cross-talk and therapeutic implications. Immunotherapy 2011; 3: 1143–1166.

    CAS  PubMed  Google Scholar 

  25. Gonzalez S, Groh V, Spies T . Immunobiology of human NKG2D and its ligands. Curr Top Microbiol Immunol 2006; 298: 121–138.

    CAS  PubMed  Google Scholar 

  26. Mamessier E, Sylvain A, Thibult ML, Houvenaeghel G, Jacquemier J, Castellano R et al. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J Clin Invest 2011; 121: 3609–3622.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Peng YP, Zhu Y, Zhang JJ, Xu ZK, Qian ZY, Dai CC et al. Comprehensive analysis of the percentage of surface receptors and cytotoxic granules positive natural killer cells in patients with pancreatic cancer, gastric cancer, and colorectal cancer. J Transl Med 2013; 11: 262.

    PubMed  PubMed Central  Google Scholar 

  28. Garcia-Iglesias T, del Toro-Arreola A, Albarran-Somoza B, del Toro-Arreola S, Sanchez-Hernandez PE, Ramirez-Duenas MG et al. Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions. BMC Cancer 2009; 9: 186.

    PubMed  PubMed Central  Google Scholar 

  29. de Kruijf EM, Sajet A, van Nes JG, Putter H, Smit VT, Eagle RA et al. NKG2D ligand tumor expression and association with clinical outcome in early breast cancer patients: an observational study. BMC Cancer 2012; 12: 24.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Shen Y, Lu C, Tian W, Wang L, Cui B, Jiao Y et al. Possible association of decreased NKG2D expression levels and suppression of the activity of natural killer cells in patients with colorectal cancer. Int J Oncol 2012; 40: 1285–1290.

    CAS  PubMed  Google Scholar 

  31. He S, Yin T, Li D, Gao X, Wan Y, Ma X et al. Enhanced interaction between natural killer cells and lung cancer cells: involvement in gefitinib-mediated immunoregulation. J Transl Med 2013; 11: 186.

    PubMed  PubMed Central  Google Scholar 

  32. Reiners KS, Topolar D, Henke A, Simhadri VR, Kessler J, Sauer M et al. Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity. Blood 2013; 121: 3658–3665.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Sanchez-Correa B, Morgado S, Gayoso I, Bergua JM, Casado JG, Arcos MJ et al. Human NK cells in acute myeloid leukaemia patients: analysis of NK cell-activating receptors and their ligands. Cancer Immunol Immunother 2011; 60: 1195–1205.

    CAS  PubMed  Google Scholar 

  34. Treon SP, Hansen M, Branagan AR, Verselis S, Emmanouilides C, Kimby E et al. Polymorphisms in FcgammaRIIIA (CD16) receptor expression are associated with clinical response to rituximab in Waldenstrom's macroglobulinemia. J Clin Oncol 2005; 23: 474–481.

    CAS  PubMed  Google Scholar 

  35. Vuletic A, Jurisic V, Jovanic I, Milovanovic Z, Nikolic S, Konjevic G . Distribution of several activating and inhibitory receptors on CD3−CD56+ NK cells in regional lymph nodes of melanoma patients. J Surg Res 2013; 183: 860–868.

    CAS  PubMed  Google Scholar 

  36. Rosental B, Hadad U, Brusilovsky M, Campbell KS, Porgador A . A novel mechanism for cancer cells to evade immune attack by NK cells: the interaction between NKp44 and proliferating cell nuclear antigen. Oncoimmunology 2012; 1: 572–574.

    PubMed  PubMed Central  Google Scholar 

  37. Bossard C, Bezieau S, Matysiak-Budnik T, Volteau C, Laboisse CL, Jotereau F et al. HLA-E/beta2 microglobulin overexpression in colorectal cancer is associated with recruitment of inhibitory immune cells and tumor progression. Int J Cancer 2012; 131: 855–863.

    CAS  PubMed  Google Scholar 

  38. Coles SJ, Wang EC, Man S, Hills RK, Burnett AK, Tonks A et al. CD200 expression suppresses natural killer cell function and directly inhibits patient anti-tumor response in acute myeloid leukemia. Leukemia 2011; 25: 792–799.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kretz-Rommel A, Qin F, Dakappagari N, Cofiell R, Faas SJ, Bowdish KS . Blockade of CD200 in the presence or absence of antibody effector function: implications for anti-CD200 therapy. J Immunol 2008; 180: 699–705.

    CAS  PubMed  Google Scholar 

  40. Kretz-Rommel A, Qin F, Dakappagari N, Ravey EP, McWhirter J, Oltean D et al. CD200 expression on tumor cells suppresses antitumor immunity: new approaches to cancer immunotherapy. J Immunol 2007; 178: 5595–5605.

    CAS  PubMed  Google Scholar 

  41. Zhang Z, Su T, He L, Wang H, Ji G, Liu X et al. Identification and functional analysis of ligands for natural killer cell activating receptors in colon carcinoma. Tohoku J Exp Med 2012; 226: 59–68.

    CAS  PubMed  Google Scholar 

  42. Bedel R, Thiery-Vuillemin A, Grandclement C, Balland J, Remy-Martin JP, Kantelip B et al. Novel role for STAT3 in transcriptional regulation of NK immune cell targeting receptor MICA on cancer cells. Cancer Res 2011; 71: 1615–1626.

    CAS  PubMed  Google Scholar 

  43. Kloess S, Huenecke S, Piechulek D, Esser R, Koch J, Brehm C et al. IL-2-activated haploidentical NK cells restore NKG2D-mediated NK-cell cytotoxicity in neuroblastoma patients by scavenging of plasma MICA. Eur J Immunol 2010; 40: 3255–3267.

    CAS  PubMed  Google Scholar 

  44. Wu JD, Atteridge CL, Wang X, Seya T, Plymate SR . Obstructing shedding of the immunostimulatory MHC class I chain-related gene B prevents tumor formation. Clin Cancer Res 2009; 15: 632–640.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Waldhauer I, Goehlsdorf D, Gieseke F, Weinschenk T, Wittenbrink M, Ludwig A et al. Tumor-associated MICA is shed by ADAM proteases. Cancer Res 2008; 68: 6368–6376.

    CAS  PubMed  Google Scholar 

  46. Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R et al. 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 USA 2003; 100: 4120–4125.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Eisele G, Wischhusen J, Mittelbronn M, Meyermann R, Waldhauer I, Steinle A et al. TGF-beta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain 2006; 129( Pt 9): 2416–2425.

    PubMed  Google Scholar 

  48. Vitale M, Cantoni C, Pietra G, Mingari MC, Moretta L . Effect of tumor cells and tumor microenvironment on NK-cell function. Eur J Immunol 2014; 44: 1582–1592.

    CAS  PubMed  Google Scholar 

  49. Farnault L, Sanchez C, Baier C, Le Treut T, Costello RT . Hematological malignancies escape from NK cell innate immune surveillance: mechanisms and therapeutic implications. Clin Dev Immunol 2012; 2012: 421702.

    PubMed  PubMed Central  Google Scholar 

  50. Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 2008; 28: 571–580.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sanchez CJ, Le Treut T, Boehrer A, Knoblauch B, Imbert J, Olive D et al. Natural killer cells and malignant haemopathies: a model for the interaction of cancer with innate immunity. Cancer Immunol Immunother 2011; 60: 1–13.

    CAS  PubMed  Google Scholar 

  52. Cerwenka A, Lanier LL . Natural killer cells, viruses and cancer. Nat Rev Immunol 2001; 1: 41–49.

    CAS  PubMed  Google Scholar 

  53. Mincheva-Nilsson L, Baranov V . Cancer exosomes and NKG2D receptor-ligand interactions: impairing NKG2D-mediated cytotoxicity and anti-tumour immune surveillance. Semin Cancer Biol 2014; in press.

  54. Morizane T, Watanabe T, Tsuchimoto K, Tsuchiya M . Impaired T cell function and decreased natural killer activity in patients with liver cirrhosis and their significance in the development of hepatocellular carcinoma. Gastroenterol Jpn 1980; 15: 226–232.

    CAS  PubMed  Google Scholar 

  55. Dunk AA, Novick D, Thomas HC . Natural killer cell activity in hepatocellular carcinoma. In vitro and in vivo responses to interferon. Scand J Gastroenterol 1987; 22: 1245–1250.

    CAS  PubMed  Google Scholar 

  56. Hirofuji H, Kakumu S, Fuji A, Ohtani Y, Murase K, Tahara H . Natural killer and activated killer activities in chronic liver disease and hepatocellular carcinoma: evidence for a decreased lymphokine-induced activity of effector cells. Clin Exp Immunol 1987; 68: 348–356.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Nakajima T, Mizushima N, Kanai K . Relationship between natural killer activity and development of hepatocellular carcinoma in patients with cirrhosis of the liver. Jpn J Clin Oncol 1987; 17: 327–332.

    CAS  PubMed  Google Scholar 

  58. Liao Y, Wang B, Huang ZL, Shi M, Yu XJ, Zheng L et al. Increased circulating Th17 cells after transarterial chemoembolization correlate with improved survival in stage III hepatocellular carcinoma: a prospective study. PloS One 2013; 8: e60444.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Cai L, Zhang Z, Zhou L, Wang H, Fu J, Zhang S et al. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin Immunol 2008; 129: 428–437.

    CAS  PubMed  Google Scholar 

  60. Fathy A, Eldin MM, Metwally L, Eida M, Abdel-Rehim M . Diminished absolute counts of CD56dim and CD56bright natural killer cells in peripheral blood from Egyptian patients with hepatocellular carcinoma. Egypt J Immunol 2009; 16: 17–25.

    PubMed  Google Scholar 

  61. Liu Y, Poon RT, Hughes J, Feng X, Yu WC, Fan ST . Chemokine receptors support infiltration of lymphocyte subpopulations in human hepatocellular carcinoma. Clin Immunol 2005; 114: 174–182.

    CAS  PubMed  Google Scholar 

  62. Guo CL, Yang HC, Yang XH, Cheng W, Dong TX, Zhu WJ et al. Associations between infiltrating lymphocyte subsets and hepatocellular carcinoma. Asian Pac J Cancer Prev 2012; 13: 5909–5913.

    PubMed  Google Scholar 

  63. Wu Y, Kuang DM, Pan WD, Wan YL, Lao XM, Wang D et al. Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions. Hepatology 2013; 57: 1107–1116.

    CAS  PubMed  Google Scholar 

  64. Peppa D, Micco L, Javaid A, Kennedy PT, Schurich A, Dunn C et al. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection. PLoS Pathog 2010; 6: e1001227.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Tjwa ET, van Oord GW, Hegmans JP, Janssen HL, Woltman AM . Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. J Hepatol 2011; 54: 209–218.

    CAS  PubMed  Google Scholar 

  66. Jinushi M, Takehara T, Tatsumi T, Hiramatsu N, Sakamori R, Yamaguchi S et al. Impairment of natural killer cell and dendritic cell functions by the soluble form of MHC class I-related chain A in advanced human hepatocellular carcinomas. J Hepatol 2005; 43: 1013–1020.

    CAS  PubMed  Google Scholar 

  67. Chuang WL, Liu HW, Chang WY . Natural killer cell activity in patients with hepatocellular carcinoma relative to early development and tumor invasion. Cancer 1990; 65: 926–930.

    CAS  PubMed  Google Scholar 

  68. Ghiringhelli F, Menard C, Terme M, Flament C, Taieb J, Chaput N et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med 2005; 202: 1075–1085.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Pietra G, Manzini C, Rivara S, Vitale M, Cantoni C, Petretto A et al. Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. Cancer Res 2012; 72: 1407–1415.

    CAS  PubMed  Google Scholar 

  70. Hayakawa Y . Targeting NKG2D in tumor surveillance. Expert Opin Ther Targets 2012; 16: 587–599.

    CAS  PubMed  Google Scholar 

  71. Wu Y, Kuang DM, Pan WD, Wan YL, Lao XM, Wang D et al. Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions. Hepatology 2013; 57: 1107–1116.

    CAS  PubMed  Google Scholar 

  72. Jia CC, Wang TT, Liu W, Fu BS, Hua X, Wang GY et al. Cancer-associated fibroblasts from hepatocellular carcinoma promote malignant cell proliferation by HGF secretion. PLoS One 2013; 8: e63243.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Li T, Yang Y, Hua X, Wang G, Liu W, Jia C et al. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett 2012; 318: 154–161.

    CAS  PubMed  Google Scholar 

  74. 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: 435–452.

    CAS  PubMed  Google Scholar 

  75. Mehal W, Imaeda A . Cell death and fibrogenesis. Semin Liver Dis 2010; 30: 226–231.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Melhem A, Muhanna N, Bishara A, Alvarez CE, Ilan Y, Bishara T et al. Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J Hepatol 2006; 45: 60–71.

    CAS  PubMed  Google Scholar 

  77. Vey N, Bourhis JH, Boissel N, Bordessoule D, Prebet T, Charbonnier A et al. A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission. Blood 2012; 120: 4317–4323.

    CAS  PubMed  Google Scholar 

  78. Benson DM Jr, Hofmeister CC, Padmanabhan S, Suvannasankha A, Jagannath S, Abonour R et al. A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma. Blood 2012; 120: 4324–4333.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Norris S, Doherty DG, Curry M, McEntee G, Traynor O, Hegarty JE et al. Selective reduction of natural killer cells and T cells expressing inhibitory receptors for MHC class I in the livers of patients with hepatic malignancy. Cancer Immunol Immunother 2003; 52: 53–58.

    CAS  PubMed  Google Scholar 

  80. Yuen MF, Norris S . Expression of inhibitory receptors in natural killer (CD3−CD56+) cells and CD3+CD56+ cells in the peripheral blood lymphocytes and tumor infiltrating lymphocytes in patients with primary hepatocellular carcinoma. Clin Immunol 2001; 101: 264–269.

    CAS  PubMed  Google Scholar 

  81. Burt BM, Plitas G, Zhao Z, Bamboat ZM, Nguyen HM, Dupont B 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: 1789–1796.

    CAS  PubMed  Google Scholar 

  82. Oliviero B, Varchetta S, Paudice E, Michelone G, Zaramella M, Mavilio D et al. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 2009; 137: 1151–1160.

    CAS  PubMed  Google Scholar 

  83. Ju Y, Hou N, Meng J, Wang X, Zhang X, Zhao D et al. T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B. J Hepatol 2010; 52: 322–329.

    CAS  PubMed  Google Scholar 

  84. Varchetta S, Mele D, Mantovani S, Oliviero B, Cremonesi E, Ludovisi S et al. Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection. Hepatology 2012; 56: 841–849.

    CAS  PubMed  Google Scholar 

  85. Bonorino P, Ramzan M, Camous X, Dufeu-Duchesne T, Thelu MA, Sturm N et al. Fine characterization of intrahepatic NK cells expressing natural killer receptors in chronic hepatitis B and C. J Hepatol 2009; 51: 458–467.

    CAS  PubMed  Google Scholar 

  86. De Maria A, Fogli M, Mazza S, Basso M, Picciotto A, Costa P 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: 445–455.

    CAS  PubMed  Google Scholar 

  87. 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: 869–877.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Meier UC, Owen RE, Taylor E, Worth A, Naoumov N, Willberg C et al. Shared alterations in NK cell frequency, phenotype, and function in chronic human immunodeficiency virus and hepatitis C virus infections. J Virol 2005; 79: 12365–12374.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Morishima C, Paschal DM, Wang CC, Yoshihara CS, Wood BL, Yeo AE et al. Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. Hepatology 2006; 43: 573–580.

    PubMed  Google Scholar 

  90. Li F, Wei H, Gao Y, Xu L, Yin W, Sun R 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: 392–401.

    CAS  PubMed  Google Scholar 

  91. Groh V, Wu J, Yee C, Spies T . Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 2002; 419: 734–738.

    CAS  PubMed  Google Scholar 

  92. Salih HR, Rammensee HG, Steinle A . Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding. J Immunol 2002; 169: 4098–4102.

    CAS  PubMed  Google Scholar 

  93. Waldhauer I, Steinle A . Proteolytic release of soluble UL16-binding protein 2 from tumor cells. Cancer Res 2006; 66: 2520–2526.

    CAS  PubMed  Google Scholar 

  94. Song H, Kim J, Cosman D, Choi I . Soluble ULBP suppresses natural killer cell activity via down-regulating NKG2D expression. Cell Immunol 2006; 239: 22–30.

    CAS  PubMed  Google Scholar 

  95. Jinushi M, Takehara T, Tatsumi T, Kanto T, Groh V, Spies T et al. Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid. Int J Cancer 2003; 104: 354–361.

    CAS  PubMed  Google Scholar 

  96. Lin H, Yan J, Wang Z, Hua F, Yu J, Sun W et al. Loss of immunity-supported senescence enhances susceptibility to hepatocellular carcinogenesis and progression in Toll-like receptor 2-deficient mice. Hepatology 2013; 57: 171–182.

    CAS  PubMed  Google Scholar 

  97. Kumar V, Yi Lo PH, Sawai H, Kato N, Takahashi A, Deng Z et al. Soluble MICA and a MICA variation as possible prognostic biomarkers for HBV-induced hepatocellular carcinoma. PLoS One 2012; 7: e44743.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Kohga K, Takehara T, Tatsumi T, Ohkawa K, Miyagi T, Hiramatsu N et al. Serum levels of soluble major histocompatibility complex (MHC) class I-related chain A in patients with chronic liver diseases and changes during transcatheter arterial embolization for hepatocellular carcinoma. Cancer Sci 2008; 99: 1643–1649.

    CAS  PubMed  Google Scholar 

  99. Kamimura H, Yamagiwa S, Tsuchiya A, Takamura M, Matsuda Y, Ohkoshi S et al. Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence. J Hepatol 2012; 56: 381–388.

    CAS  PubMed  Google Scholar 

  100. Zhang C, Zhang J, Niu J, Tian Z . Interleukin-15 improves cytotoxicity of natural killer cells via up-regulating NKG2D and cytotoxic effector molecule expression as well as STAT1 and ERK1/2 phosphorylation. Cytokine 2008; 42: 128–136.

    CAS  PubMed  Google Scholar 

  101. Chretien AS, Le Roy A, Vey N, Prebet T, Blaise D, Fauriat C et al. Cancer-induced alterations of NK-mediated target recognition: current and investigational pharmacological strategies aiming at restoring NK-mediated anti-tumor activity. Front Immunol 2014; 5: 122.

    PubMed  PubMed Central  Google Scholar 

  102. Raulet DH, Gasser S, Gowen BG, Deng W, Jung H . Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol 2013; 31: 413–441.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Zhang C, Zhang J, Sun R, Feng J, Wei H, Tian Z . Opposing effect of IFNgamma and IFNalpha on expression of NKG2 receptors: negative regulation of IFNgamma on NK cells. Int Immunopharmacol 2005; 5: 1057–1067.

    CAS  PubMed  Google Scholar 

  104. Zhang C, Niu J, Zhang J, Wang Y, Zhou Z, Tian Z . Opposing effects of interferon-alpha and interferon-gamma on the expression of major histocompatibility complex class I chain-related A in tumors. Cancer Sci 2008; 99: 1279–1286.

    CAS  PubMed  Google Scholar 

  105. Zhou H, Huang H, Shi J, Zhao Y, Dong Q, Jia H et al. Prognostic value of interleukin 2 and interleukin 15 in peritumoral hepatic tissues for patients with hepatitis B-related hepatocellular carcinoma after curative resection. Gut 2010; 59: 1699–1708.

    PubMed  Google Scholar 

  106. Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A et al. Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol 2010; 52: 370–379.

    CAS  PubMed  Google Scholar 

  107. Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 2006; 10: 99–111.

    CAS  PubMed  Google Scholar 

  108. Fransvea E, Mazzocca A, Santamato A, Azzariti A, Antonaci S, Giannelli G . Kinase activation profile associated with TGF-beta-dependent migration of HCC cells: a preclinical study. Cancer Chemother Pharmacol 2011; 68: 79–86.

    CAS  PubMed  Google Scholar 

  109. Dituri F, Mazzocca A, Peidro FJ, Papappicco P, Fabregat I, de Santis F et al. Differential inhibition of the TGF-beta signaling pathway in HCC cells using the small molecule inhibitor LY2157299 and the D10 monoclonal antibody against TGF-beta receptor type II. PLoS One 2013; 8: e67109.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Wilson EB, El-Jawhari JJ, Neilson AL, Hall GD, Melcher AA, Meade JL et al. Human tumour immune evasion via TGF-beta blocks NK cell activation but not survival allowing therapeutic restoration of anti-tumour activity. PLoS One 2011; 6: e22842.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Lee JC, Lee KM, Kim DW, Heo DS . Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol 2004; 172: 7335–7340.

    CAS  PubMed  Google Scholar 

  112. Sun C, Fu B, Gao Y, Liao X, Sun R, Tian Z et al. TGF-beta1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence. PLoS Pathog 2012; 8: e1002594.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Ghiringhelli F, Menard C, Martin F, Zitvogel L . The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression. Immunol Rev 2006; 214: 229–238.

    CAS  PubMed  Google Scholar 

  114. Bergmann C, Wild CA, Narwan M, Lotfi R, Lang S, Brandau S . Human tumor-induced and naturally occurring Treg cells differentially affect NK cells activated by either IL-2 or target cells. Eur J Immunol 2011; 41: 3564–3573.

    CAS  PubMed  Google Scholar 

  115. Sprinzl MF, Reisinger F, Puschnik A, Ringelhan M, Ackermann K, Hartmann D et al. Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells. Hepatology 2013; 57: 2358–2368.

    CAS  PubMed  Google Scholar 

  116. Balsamo M, Scordamaglia F, Pietra G, Manzini C, Cantoni C, Boitano M et al. Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc Natl Acad Sci USA 2009; 106: 20847–20852.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Tsunematsu H, Tatsumi T, Kohga K, Yamamoto M, Aketa H, Miyagi T et al. Fibroblast growth factor-2 enhances NK sensitivity of hepatocellular carcinoma cells. Int J Cancer 2012; 130: 356–364.

    CAS  PubMed  Google Scholar 

  118. Maghazachi AA . Role of chemokines in the biology of natural killer cells. Curr Top Microbiol Immunol 2010; 341: 37–58.

    CAS  PubMed  Google Scholar 

  119. Iannello A, Thompson TW, Ardolino M, Lowe SW, Raulet DH . p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J Exp Med 2013; 210: 2057–2069.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Waggoner SN, Daniels KA, Welsh RM . Therapeutic depletion of natural killer cells controls persistent infection. J Virol 2014; 88: 1953–1960.

    PubMed  PubMed Central  Google Scholar 

  121. Peppa D, Gill US, Reynolds G, Easom NJ, Pallett LJ, Schurich A et al. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp Med 2013; 210: 99–114.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Gehring AJ, Ho ZZ, Tan AT, Aung MO, Lee KH, Tan KC et al. Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma. Gastroenterology 2009; 137: 682–690.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Chinese Government Department of Science & Technology of China (2012ZX10002006; 2012ZX10002014; 2013ZX10002002; 2012AA020901; 2010CB911901; 2013CB944901) and the Natural Science Foundation of China (81273220; 81472646).

Author information

Author notes

  1. Dr C Zhang, Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, China. E-mail: caizhangsd@sdu.edu.cn

  2. Dr ZG Tian, Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China. E-mail: tzg@ustc.edu.cn

Authors and Affiliations

  1. Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China

    Cheng Sun, Haoyu Sun & Zhigang Tian

  2. Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, China

    Cai Zhang

Authors
  1. Cheng Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haoyu Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cai Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhigang Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, C., Sun, H., Zhang, C. et al. NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma. Cell Mol Immunol 12, 292–302 (2015). https://doi.org/10.1038/cmi.2014.91

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2014.91

Keywords

This article is cited by

Search

Advanced search

Quick links