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Natural killer cells in hepatocellular carcinoma: current status and perspectives for future immunotherapeutic approaches

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Abstract

Hepatocellular carcinoma (HCC) is currently the fifth most common malignancy and the third leading cause of cancer-related mortalities worldwide. In the last few years, treatments for HCC have significantly improved from a mere surgical resection to a series of minimally invasive therapies and targeted drugs. However, recurrence frequently occurs even upon curative therapeutics, and drug therapies generally produce disappointing results, with the overall prognosis dismal. This challenging clinical scenario warrants new effective and life-prolonging strategies for patients with HCC. Compelling evidence suggests that NK cells play a critical role in the immune function of the liver and in the immune defenses against HCC, indicating that HCC might be an ideal target for NK cell-based immunotherapies. To obtain comprehensive insights into the putative influence of NK cells on HCC, this paper summarizes current knowledge on NK cells in HCC and discusses the usefulness and prospects of NK cell-based immunotherapies. Critical issues that require consideration for the successful clinical translation of NK cell-based therapies are also addressed. If appropriately used and further optimized, NK cell-based therapies could dominate important roles in the future immunotherapeutic market of HCC.

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References

  1. Maluccio M, Covey A. Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA Cancer J Clin 2012; 62(6): 394–399

    Article  PubMed  Google Scholar 

  2. Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology 2016; 150(4): 835–853

    Article  PubMed  Google Scholar 

  3. Forner A, Gilabert M, Bruix J, Raoul JL. Treatment of intermediate-stage hepatocellular carcinoma. Nat Rev Clin Oncol 2014; 11(9): 525–535

    Article  CAS  PubMed  Google Scholar 

  4. Sieghart W, Hucke F, Peck-Radosavljevic M. Transarterial chemoembolization: modalities, indication, and patient selection. J Hepatol 2015; 62(5): 1187–1195

    Article  PubMed  Google Scholar 

  5. Llovet JM, Villanueva A, Lachenmayer A, Finn RS. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol 2015; 12(7): 408–424

    Article  CAS  PubMed  Google Scholar 

  6. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011; 480(7378): 480–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol 2008; 9(5): 503–510

    Article  CAS  PubMed  Google Scholar 

  8. Martinet L, Smyth MJ. Balancing natural killer cell activation through paired receptors. Nat Rev Immunol 2015; 15(4): 243–254

    Article  CAS  PubMed  Google Scholar 

  9. Herberman RB, Reynolds CW, Ortaldo JR. Mechanism of cytotoxicity by natural killer (NK) cells. Annu Rev Immunol 1986; 4(1): 651–680

    Article  CAS  PubMed  Google Scholar 

  10. Orange JS. Formation and function of the lytic NK-cell immunological synapse. Nat Rev Immunol 2008; 8(9): 713–725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. de Saint Basile G, Ménasché G, Fischer A. Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat Rev Immunol 2010; 10(8): 568–579

    Article  PubMed  CAS  Google Scholar 

  12. Wang W, Erbe AK, Hank JA, Morris ZS, Sondel PMNK. NK cellmediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Front Immunol 2015; 6: 368

    PubMed  PubMed Central  Google Scholar 

  13. Igarashi T, Wynberg J, Srinivasan R, Becknell B, McCoy JP Jr, Takahashi Y, Suffredini DA, Linehan WM, Caligiuri MA, Childs RW. Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells. Blood 2004; 104(1): 170–177

    Article  CAS  PubMed  Google Scholar 

  14. Willemze R, Rodrigues CA, Labopin M, Sanz G, Michel G, Socié G, Rio B, Sirvent A, Renaud M, Madero L, Mohty M, Ferra C, Garnier F, Loiseau P, Garcia J, Lecchi L, Kögler G, Beguin Y, Navarrete C, Devos T, Ionescu I, Boudjedir K, Herr AL, Gluckman E, Rocha V; Eurocord-Netcord and Acute Leukaemia Working Party of the EBMT. KIR-ligand incompatibility in the graft-versushost direction improves outcomes after umbilical cord blood transplantation for acute leukemia. Leukemia 2009; 23(3): 492–500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rubnitz JE, Inaba H, Ribeiro RC, Pounds S, Rooney B, Bell T, Pui CH, Leung W. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J Clin Oncol 2010; 28(6): 955–959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, Iwakura Y, Yagita H, Okumura K. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 2001; 7(1): 94–100

    Article  CAS  PubMed  Google Scholar 

  17. Shi FD, Ljunggren HG, La Cava A, Van Kaer L. Organ-specific features of natural killer cells. Nat Rev Immunol 2011; 11(10): 658–671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chew V, Chen J, Lee D, Loh E, Lee J, Lim KH, Weber A, Slankamenac K, Poon RT, Yang H, Ooi LL, Toh HC, Heikenwalder M, Ng IO, Nardin A, Abastado JP. Chemokinedriven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma. Gut 2012; 61(3): 427–438

    Article  CAS  PubMed  Google Scholar 

  19. 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(2): 362–372

    Article  CAS  PubMed  Google Scholar 

  20. Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, Loh M, Bolze A, Quek R, Lee VK, Lee KH, Abastado JP, Toh HC, Nardin A. Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol 2010; 52(3): 370–379

    Article  CAS  PubMed  Google Scholar 

  21. Marengo A, Rosso C, Bugianesi E. Liver cancer: connections with obesity, fatty liver, and cirrhosis. Annu Rev Med 2016; 67: 103–117

    Article  CAS  PubMed  Google Scholar 

  22. Tian Z, Chen Y, Gao B. Natural killer cells in liver disease. Hepatology 2013; 57(4): 1654–1662

    Article  CAS  PubMed  Google Scholar 

  23. Coulouarn C, Factor VM, Conner EA, Thorgeirsson SS. Genomic modeling of tumor onset and progression in a mouse model of aggressive human liver cancer. Carcinogenesis 2011; 32(10): 1434–1440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cai L, Zhang Z, Zhou L, Wang H, Fu J, Zhang S, Shi M, Zhang H, Yang Y, Wu H, Tien P, Wang FS. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin Immunol 2008; 129(3): 428–437

    Article  CAS  PubMed  Google Scholar 

  25. Gao B, Radaeva S, Park O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J Leukoc Biol 2009; 86(3): 513–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. He L, Wang X, Montell DJ. Shining light on Drosophila oogenesis: live imaging of egg development. Curr Opin Genet Dev 2011; 21(5): 612–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chirinda W, Chen H. Comparative study of disability-free life expectancy across six low- and middle-income countries. Geriatr Gerontol Int 2017; 17(4): 637–644

    Article  PubMed  Google Scholar 

  28. Une Y, Kawata A, Uchino J. Adopted immunochemotherapy using IL-2 and spleen LAK cell—randomized study. Nihon Geka Gakkai Zasshi 1991; 92(9): 1330–1333 (in Japanese)

    CAS  PubMed  Google Scholar 

  29. Lygidakis NJ, Pothoulakis J, Konstantinidou AE, Spanos H. Hepatocellular carcinoma: surgical resection versus surgical resection combined with pre- and post-operative locoregional immunotherapy-chemotherapy. A prospective randomized study. Anticancer Res 1995; 15(2): 543–550

    CAS  PubMed  Google Scholar 

  30. Kawata A, Une Y, Hosokawa M, Wakizaka Y, Namieno T, Uchino J, Kobayashi H. Adjuvant chemoimmunotherapy for hepatocellular carcinoma patients. Adriamycin, interleukin-2, and lymphokine- activated killer cells versus adriamycin alone. Am J Clin Oncol 1995; 18(3): 257–262

    Article  CAS  PubMed  Google Scholar 

  31. Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol 2013; 31(1): 227–258

    Article  CAS  PubMed  Google Scholar 

  32. Beneker C. Report from Hannover. Family practitioners in emergency admission. MMW Fortschr Med 2015; 157(1): 8–9 (in German)

    Article  PubMed  Google Scholar 

  33. Lanier LL. NK cell recognition. Annu Rev Immunol 2005; 23(1): 225–274

    Article  CAS  PubMed  Google Scholar 

  34. Woo SR, Corrales L, Gajewski TF. Innate immune recognition of cancer. Annu Rev Immunol 2015; 33(1): 445–474

    Article  CAS  PubMed  Google Scholar 

  35. Guillerey C, Huntington ND, Smyth MJ. Targeting natural killer cells in cancer immunotherapy. Nat Immunol 2016; 17(9): 1025–1036

    Article  CAS  PubMed  Google Scholar 

  36. Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 2003; 3(10): 781–790

    Article  CAS  PubMed  Google Scholar 

  37. Eagle RA, Trowsdale J. Promiscuity and the single receptor: NKG2D. Nat Rev Immunol 2007; 7(9): 737–744

    Article  CAS  PubMed  Google Scholar 

  38. Jinushi M, Takehara T, Tatsumi T, Hiramatsu N, Sakamori R, Yamaguchi S, Hayashi N. 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(6): 1013–1020

    Article  CAS  PubMed  Google Scholar 

  39. Kamimura H, Yamagiwa S, Tsuchiya A, Takamura M, Matsuda Y, Ohkoshi S, Inoue M, Wakai T, Shirai Y, Nomoto M, Aoyagi Y. Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence. J Hepatol 2012; 56(2): 381–388

    Article  CAS  PubMed  Google Scholar 

  40. Gao J, Duan Z, Zhang L, Huang X, Long L, Tu J, Liang H, Zhang Y, Shen T, Lu F. Failure recovery of circulating NKG2D(+)CD56 (dim)NK cells in HBV-associated hepatocellular carcinoma after hepatectomy predicts early recurrence. OncoImmunology 2016; 5(1): e1048061

    Article  PubMed  CAS  Google Scholar 

  41. Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H, Lehner F, Manns MP, Greten TF, Korangy F. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 2009; 50(3): 799–807

    Article  CAS  PubMed  Google Scholar 

  42. Qu P, Huang X, Zhou X, Lü Z, Liu F, Shi Z, Lü L, Wu Y, Chen Y. Loss of CD155 expression predicts poor prognosis in hepatocellular carcinoma. Histopathology 2015; 66(5): 706–714

    Article  PubMed  Google Scholar 

  43. Tanimine N, Ohdan H. Impact of multiplicity of functional KIRHLA compound genotypes on hepatocellular carcinoma. OncoImmunology 2015; 4(1): e983765

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Vilches C, Parham P. KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol 2002; 20(1): 217–251

    Article  CAS  PubMed  Google Scholar 

  45. Raulet DH, Vance RE, McMahon CW. Regulation of the natural killer cell receptor repertoire. Annu Rev Immunol 2001; 19(1): 291–330

    Article  CAS  PubMed  Google Scholar 

  46. Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, Song YJ, Yang L, French AR, Sunwoo JB, Lemieux S, Hansen TH, Yokoyama WM. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 2005; 436(7051): 709–713

    Article  CAS  PubMed  Google Scholar 

  47. Cariani E, Pilli M, Zerbini A, Rota C, Olivani A, Zanelli P, Zanetti A, Trenti T, Ferrari C, Missale G. HLA and killer immunoglobulinlike receptor genes as outcome predictors of hepatitis C virusrelated hepatocellular carcinoma. Clin Cancer Res 2013; 19(19): 5465–5473

    Article  CAS  PubMed  Google Scholar 

  48. Tanimine N, Tanaka Y, Kobayashi T, Tashiro H, Miki D, Imamura M, Aikata H, Tanaka J, Chayama K, Ohdan H. Quantitative effect of natural killer-cell licensing on hepatocellular carcinoma recurrence after curative hepatectomy. Cancer Immunol Res 2014; 2(12): 1142–1147

    Article  CAS  PubMed  Google Scholar 

  49. Singh R, Kaul R, Kaul A, Khan K. A comparative review of HLA associations with hepatitis B and C viral infections across global populations. World J Gastroenterol 2007; 13(12): 1770–1787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jamil KM, Khakoo SI. KIR/HLA interactions and pathogen immunity. J Biomed Biotechnol 2011; 2011: 298348

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Pan N, Jiang W, Sun H, Miao F, Qiu J, Jin H, Xu J, Shi Q, Xie W, Zhang J. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 2006; 1(1): 23–61

    Article  CAS  PubMed  Google Scholar 

  53. Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol 2016; 16(8): 509–523

    Article  CAS  PubMed  Google Scholar 

  54. Pan N, Qiu J, Sun H, Miao F, Shi Q, Xu J, Jiang W, Jin H, Xie W, He Y, Zhang J. Combination of human leukecyte antigen and killer cell immunoglulin-like antigen and killer cell influences the onset age of hepatocellular carcinoma in male patients with hepatitis B virus infenction. Clin Dev Immunol 2013; 2013: 874514

    PubMed  PubMed Central  Google Scholar 

  55. De Re V, Caggiari L, De Zorzi M, Repetto O, Zignego AL, Izzo F, Tornesello ML, Buonaguro FM, Mangia A, Sansonno D, Racanelli V, De Vita S, Pioltelli P, Vaccher E, Berretta M, Mazzaro C, Libra M, Gini A, Zucchetto A, Cannizzaro R, De Paoli P. Genetic diversity of the KIR/HLA system and susceptibility to hepatitis C virus-related diseases. PLoS One 2015; 10(2): e0117420

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011; 331(6024): 1565–1570

    Article  CAS  PubMed  Google Scholar 

  57. Chan SL, Mo FK, Wong CS, Chan CM, Leung LK, Hui EP, Ma BB, Chan AT, Mok TS, Yeo W. A study of circulating interleukin 10 in prognostication of unresectable hepatocellular carcinoma. Cancer 2012; 118(16): 3984–3992

    Article  CAS  PubMed  Google Scholar 

  58. Chen Z, Xie B, Zhu Q, Xia Q, Jiang S, Cao R, Shi L, Qi D, Li X, Cai L. FGFR4 and TGF-β1 expression in hepatocellular carcinoma: correlation with clinicopathological features and prognosis. Int J Med Sci 2013; 10(13): 1868–1875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Makarova-Rusher OV, Medina-Echeverz J, Duffy AG, Greten TF. The yin and yang of evasion and immune activation in HCC. J Hepatol 2015; 62(6): 1420–1429

    Article  CAS  PubMed  Google Scholar 

  60. Lin TH, Shao YY, Chan SY, Huang CY, Hsu CH, Cheng AL. High serum transforming growth factor-β1 levels predict outcome in hepatocellular carcinoma patients treated with sorafenib. Clin Cancer Res 2015; 21(16): 3678–3684

    Article  CAS  PubMed  Google Scholar 

  61. Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol 2013; 14(6): e218–e228

    Article  CAS  PubMed  Google Scholar 

  62. Mouri H, Sakaguchi K, Sawayama T, Senoh T, Ohta T, Nishimura M, Fujiwara A, Terao M, Shiratori Y, Tsuji T. Suppressive effects of transforming growth factor-beta1 produced by hepatocellular carcinoma cell lines on interferon-γ production by peripheral blood mononuclear cells. Acta Med Okayama 2002; 56(6): 309–315

    CAS  PubMed  Google Scholar 

  63. Sui Q, Zhang J, Sun X, Zhang C, Han Q, Tian Z. NK cells are the crucial antitumor mediators when STAT3-mediated immunosuppression is blocked in hepatocellular carcinoma. J Immunol 2014; 193(4): 2016–2023

    Article  CAS  PubMed  Google Scholar 

  64. Xu D, Han Q, Hou Z, Zhang C, Zhang J. miR-146a negatively regulates NK cell functions via STAT1 signaling. Cell Mol Immunol 2016 Mar 21. [Epub ahead of print] doi: 10.1038/cmi.2015.113

    Google Scholar 

  65. Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 2013; 144(3): 512–527

    Article  PubMed  Google Scholar 

  66. Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, Zhang Z, Yang H, Zhang H, Zhou C, Yao J, Jin L, Wang H, Yang Y, Fu YX, Wang FS. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 2007; 132(7): 2328–2339

    Article  PubMed  Google Scholar 

  67. Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007; 25(18): 2586–2593

    Article  PubMed  Google Scholar 

  68. Langhans B, Alwan AW, Krämer B, Glässner A, Lutz P, Strassburg CP, Nattermann J, Spengler U. Regulatory CD4+ T cells modulate the interaction between NK cells and hepatic stellate cells by acting on either cell type. J Hepatol 2015; 62(2): 398–404

    Article  CAS  PubMed  Google Scholar 

  69. Parker KH, Beury DW, Ostrand-Rosenberg S. Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res 2015; 128: 95–139

    Article  PubMed  PubMed Central  Google Scholar 

  70. Wan S, Kuo N, Kryczek I, Zou W, Welling TH. Myeloid cells in hepatocellular carcinoma. Hepatology 2015; 62(4): 1304–1312

    Article  PubMed  Google Scholar 

  71. Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 2008; 8(9): 705–713

    Article  CAS  PubMed  Google Scholar 

  72. Nizet V, Johnson RS. Interdependence of hypoxic and innate immune responses. Nat Rev Immunol 2009; 9(9): 609–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hasmim M, Messai Y, Ziani L, Thiery J, Bouhris JH, Noman MZ, Chouaib S. Critical role of tumor microenvironment in shaping NK cell functions: implication of hypoxic stress. Front Immunol 2015; 6: 482

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Zerbini A, Pilli M, Penna A, Pelosi G, Schianchi C, Molinari A, Schivazappa S, Zibera C, Fagnoni FF, Ferrari C, Missale G. Radiofrequency thermal ablation of hepatocellular carcinoma liver nodules can activate and enhance tumor-specific T-cell responses. Cancer Res 2006; 66(2): 1139–1146

    Article  CAS  PubMed  Google Scholar 

  75. Mizukoshi E, Yamashita T, Arai K, Sunagozaka H, Ueda T, Arihara F, Kagaya T, Yamashita T, Fushimi K, Kaneko S. Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology 2013; 57(4): 1448–1457

    Article  CAS  PubMed  Google Scholar 

  76. Zerbini A, Pilli M, Laccabue D, Pelosi G, Molinari A, Negri E, Cerioni S, Fagnoni F, Soliani P, Ferrari C, Missale G. Radiofrequency thermal ablation for hepatocellular carcinoma stimulates autologous NK-cell response. Gastroenterology 2010; 138(5): 1931–1942

    Article  CAS  PubMed  Google Scholar 

  77. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359(4): 378–390

    Article  CAS  PubMed  Google Scholar 

  78. Tomuleasa C, Giannelli G, Cucuianu A, Aldea M, Paradiso A, Berindan-Neagoe I. Interplay between cancer cells, macrophages and natural killer cells may actually decide the outcome of therapy with sorafenib. Hepatology 2014; 60(1): 430

    Article  CAS  PubMed  Google Scholar 

  79. Kohga K, Takehara T, Tatsumi T, Ishida H, Miyagi T, Hosui A, Hayashi N. Sorafenib inhibits the shedding of major histocompatibility complex class I-related chain A on hepatocellular carcinoma cells by down-regulating a disintegrin and metalloproteinase 9. Hepatology 2010; 51(4): 1264–1273

    Article  CAS  PubMed  Google Scholar 

  80. Zhang QB, Sun HC, Zhang KZ, Jia QA, Bu Y, Wang M, Chai ZT, Zhang QB, Wang WQ, Kong LQ, Zhu XD, Lu L, Wu WZ, Wang L, Tang ZY. Suppression of natural killer cells by sorafenib contributes to prometastatic effects in hepatocellular carcinoma. PLoS One 2013; 8(2): e55945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Sprinzl MF, Reisinger F, Puschnik A, Ringelhan M, Ackermann K, Hartmann D, Schiemann M, Weinmann A, Galle PR, Schuchmann M, Friess H, Otto G, Heikenwalder M, Protzer U. Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells. Hepatology 2013; 57(6): 2358–2368

    Article  CAS  PubMed  Google Scholar 

  82. Kamiya T, Chang YH, Campana D. Expanded and activated natural killer cells for immunotherapy of hepatocellular carcinoma. Cancer Immunol Res 2016; 4(7): 574–581

    Article  CAS  PubMed  Google Scholar 

  83. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9(11): 798–809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 2007; 7(1): 41–51

    Article  CAS  PubMed  Google Scholar 

  85. Armeanu S, Krusch M, Baltz KM, Weiss TS, Smirnow I, Steinle A, Lauer UM, Bitzer M, Salih HR. Direct and natural killer cellmediated antitumor effects of low-dose bortezomib in hepatocellular carcinoma. Clin Cancer Res 2008; 14(11): 3520–3528

    Article  CAS  PubMed  Google Scholar 

  86. Shi L, Lin H, Li G, Sun Y, Shen J, Xu J, Lin C, Yeh S, Cai X, Chang C. Cisplatin enhances NK cells immunotherapy efficacy to suppress HCC progression via altering the androgen receptor (AR)-ULBP2 signals. Cancer Lett 2016; 373(1): 45–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2015; 12(12): 681–700

    Article  CAS  PubMed  Google Scholar 

  88. Takeda T, Watanabe M, Umeshita K, Goto M, Monden M. Longterm prognosis of hepatocellular carcinoma patients treated with adoptive immunotherapy. Gan To Kagaku Ryoho 2004; 31(11): 1646–1648 (in Japanese)

    PubMed  Google Scholar 

  89. Hsieh KH, Chang JS, Wu HL, Chu CT. Interleukin 2 and lymphokine-activated killer cells in the treatment of childhood primary hepatocellular carcinoma—a preliminary report. Asian Pac J Allergy Immunol 1987; 5(1): 13–16

    CAS  PubMed  Google Scholar 

  90. Huang ZM, Li W, Li S, Gao F, Zhou QM, Wu FM, He N, Pan CC, Xia JC, Wu PH, Zhao M. Cytokine-induced killer cells in combination with transcatheter arterial chemoembolization and radiofrequency ablation for hepatocellular carcinoma patients. J Immunother 2013; 36(5): 287–293

    Article  PubMed  Google Scholar 

  91. Xu L, Wang J, Kim Y, Shuang ZY, Zhang YJ, Lao XM, Li YQ, Chen MS, Pawlik TM, Xia JC, Li SP, Lau WY. A randomized controlled trial on patients with or without adjuvant autologous cytokine-induced killer cells after curative resection for hepatocellular carcinoma. OncoImmunology 2015; 5(3): e1083671

    Article  PubMed  PubMed Central  Google Scholar 

  92. Li X, Dai D, Song X, Liu J, Zhu L, Xu W. A meta-analysis of cytokine-induced killer cells therapy in combination with minimally invasive treatment for hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2014; 38(5): 583–591

    Article  CAS  PubMed  Google Scholar 

  93. He G, Zheng C, Huo H, Zhang H, Zhu Z, Li J, Zhang H. TACE combined with dendritic cells and cytokine-induced killer cells in the treatment of hepatocellular carcinoma: a meta-analysis. Int Immunopharmacol 2016; 40: 436–442

    Article  CAS  PubMed  Google Scholar 

  94. Lee JH, Lee JH, Lim YS, Yeon JE, Song TJ, Yu SJ, Gwak GY, Kim KM, Kim YJ, Lee JW, Yoon JH. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 2015; 148(7): 1383–91.e6

    Article  CAS  PubMed  Google Scholar 

  95. Fujisaki H, Kakuda H, Shimasaki N, Imai C, Ma J, Lockey T, Eldridge P, Leung WH, Campana D. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res 2009; 69(9): 4010–4017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Granzin M, Soltenborn S, Müller S, Kollet J, Berg M, Cerwenka A, Childs RW, Huppert V. Fully automated expansion and activation of clinical-grade natural killer cells for adoptive immunotherapy. Cytotherapy 2015; 17(5): 621–632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lim O, Jung MY, Hwang YK, Shin EC. Present and future of allogeneic natural killer cell therapy. Front Immunol 2015; 6: 286

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295(5562): 2097–2100

    Article  CAS  PubMed  Google Scholar 

  99. Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, McKenna D, Le C, Defor TE, Burns LJ, Orchard PJ, Blazar BR, Wagner JE, Slungaard A, Weisdorf DJ, Okazaki IJ, McGlave PB. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005; 105(8): 3051–3057

    Article  CAS  PubMed  Google Scholar 

  100. Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000; 356(9232): 802–807

    Article  CAS  PubMed  Google Scholar 

  101. Ochi M, Ohdan H, Mitsuta H, Onoe T, Tokita D, Hara H, Ishiyama K, Zhou W, Tanaka Y, Asahara T. Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice. Hepatology 2004; 39(5): 1321–1331

    Article  CAS  PubMed  Google Scholar 

  102. Nishida S, Levi DM, Tzakis AG. Liver natural killer cell inoculum for liver transplantation with hepatocellular carcinoma. Curr Opin Organ Transplant 2013; 18(6): 690–694

    CAS  PubMed  Google Scholar 

  103. Suck G, Odendahl M, Nowakowska P, Seidl C, Wels WS, Klingemann HG, Tonn T. NK-92: an ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother 2016; 65(4): 485–492

    Article  CAS  PubMed  Google Scholar 

  104. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12(4): 252–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hato T, Goyal L, Greten TF, Duda DG, Zhu AX. Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology 2014; 60(5): 1776–1782

    Article  CAS  PubMed  Google Scholar 

  106. Pesce S, Greppi M, Tabellini G, Rampinelli F, Parolini S, Olive D, Moretta L, Moretta A, Marcenaro E. Identification of a subset of human natural killer cells expressing high levels of programmed death 1: a phenotypic and functional characterization. J Allergy Clin Immunol 2017; 139(1): 335–346.e3

    Article  CAS  PubMed  Google Scholar 

  107. Korde N, Carlsten M, Lee MJ, Minter A, Tan E, Kwok M, Manasanch E, Bhutani M, Tageja N, Roschewski M, Zingone A, Costello R, Mulquin M, Zuchlinski D, Maric I, Calvo KR, Braylan R, Tembhare P, Yuan C, Stetler-Stevenson M, Trepel J, Childs R, Landgren O. A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma. Haematologica 2014; 99(6): e81–e83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Carlsten M, Korde N, Kotecha R, Reger R, Bor S, Kazandjian D, Landgren O, Childs RW. Checkpoint inhibition of KIR2D with the monoclonal antibody IPH2101 induces contraction and hyporesponsiveness of NK cells in patients with myeloma. Clin Cancer Res 2016; 22(21): 5211–5222

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  109. Felices M, Miller JS. Targeting KIR blockade in multiple myeloma: trouble in checkpoint paradise? Clin Cancer Res 2016; 22(21): 5161–5163

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Ruggeri L, Urbani E, André P, Mancusi A, Tosti A, Topini F, Bléry M, Animobono L, Romagné F, Wagtmann N, Velardi A. Effects of anti-NKG2A antibody administration on leukemia and normal hematopoietic cells. Haematologica 2016; 101(5): 626–633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Chen A, Shen Y, Xia M, Xu L, Pan N, Yin Y, Miao F, Shen C, Xie W, Zhang J. Expression of the nonclassical HLA class I and MICA/ B molecules in human hepatocellular carcinoma. Neoplasma 2011; 58(5): 371–376

    Article  CAS  PubMed  Google Scholar 

  112. Casadevall A, Pirofski LA. A new synthesis for antibody-mediated immunity. Nat Immunol 2011; 13(1): 21–28

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Capurro M, Wanless IR, Sherman M, Deboer G, Shi W, Miyoshi E, Filmus J. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology 2003; 125(1): 89–97

    Article  CAS  PubMed  Google Scholar 

  114. Nakano K, Orita T, Nezu J, Yoshino T, Ohizumi I, Sugimoto M, Furugaki K, Kinoshita Y, Ishiguro T, Hamakubo T, Kodama T, Aburatani H, Yamada-Okabe H, Tsuchiya M. Anti-glypican 3 antibodies cause ADCC against human hepatocellular carcinoma cells. Biochem Biophys Res Commun 2009; 378(2): 279–284

    Article  CAS  PubMed  Google Scholar 

  115. Zhu AX, Gold PJ, El-Khoueiry AB, Abrams TA, Morikawa H, Ohishi N, Ohtomo T, Philip PA. First-in-man phase I study of GC33, a novel recombinant humanized antibody against glypican-3, in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2013; 19(4): 920–928

    Article  CAS  PubMed  Google Scholar 

  116. Felices M, Lenvik TR, Davis ZB, Miller JS, Vallera DA. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. Methods Mol Biol 2016; 1441: 333–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Tay SS, Carol H, Biro M. TriKEs and BiKEs join CARs on the cancer immunotherapy highway. Hum Vaccin Immunother 2016; 12(11): 2790–2796

    Article  PubMed  PubMed Central  Google Scholar 

  118. Vallera DA, Felices M, McElmurry R, McCullar V, Zhou X, Schmohl JU, Zhang B, Lenvik AJ, Panoskaltsis-Mortari A, Verneris MR, Tolar J, Cooley S, Weisdorf DJ, Blazar BR, Miller JS. IL15 trispecific killer engagers (TriKE) make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Clin Cancer Res 2016; 22(14): 3440–3450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Schmohl JU, Felices M, Taras E, Miller JS, Vallera DA. Enhanced ADCC and NK cell activation of an anticarcinoma bispecific antibody by genetic insertion of a modified IL-15 cross-linker. Mol Ther 2016; 24(7): 1312–1322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Mariani E, Meneghetti A, Tarozzi A, Cattini L, Facchini A. Interleukin-12 induces efficient lysis of natural killer-sensitive and natural killer-resistant human osteosarcoma cells: the synergistic effect of interleukin-2. Scand J Immunol 2000; 51(6): 618–625

    Article  CAS  PubMed  Google Scholar 

  121. Jiang W, Zhang C, Tian Z, Zhang J. hIFN-α gene modification augments human natural killer cell line anti-human hepatocellular carcinoma function. Gene Ther 2013; 20(11): 1062–1069

    Article  CAS  PubMed  Google Scholar 

  122. Jiang W, Zhang C, Tian Z, Zhang J. hIL-15 gene-modified human natural killer cells (NKL-IL15) augments the anti-human hepatocellular carcinoma effect in vivo. Immunobiology 2014; 219(7): 547–553

    Article  CAS  PubMed  Google Scholar 

  123. Chang YH, Connolly J, Shimasaki N, Mimura K, Kono K, Campana D. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. Cancer Res 2013; 73(6): 1777–1786

    Article  CAS  PubMed  Google Scholar 

  124. Hermanson DL, Kaufman DS. Utilizing chimeric antigen receptors to direct natural killer cell activity. Front Immunol 2015; 6: 195

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Klingemann H. Are natural killer cells superior CAR drivers? OncoImmunology 2014; 3(4): e28147

    Article  PubMed  PubMed Central  Google Scholar 

  126. Esser R, Müller T, Stefes D, Kloess S, Seidel D, Gillies SD, Aperlo-Iffland C, Huston JS, Uherek C, Schönfeld K, Tonn T, Huebener N, Lode HN, Koehl U, Wels WS. NK cells engineered to express a GD2-specific antigen receptor display built-in ADCClike activity against tumour cells of neuroectodermal origin. J Cell Mol Med 2012; 16(3): 569–581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Boissel L, Betancur-Boissel M, Lu W, Krause DS, Van Etten RA, Wels WS, Klingemann H. Retargeting NK-92 cells by means of CD19- and CD20-specific chimeric antigen receptors compares favorably with antibody-dependent cellular cytotoxicity. OncoImmunology 2013; 2(10): e26527

    Article  PubMed  PubMed Central  Google Scholar 

  128. Zhang C, Burger MC, Jennewein L, Genßler S, Schönfeld K, Zeiner P, Hattingen E, Harter PN, Mittelbronn M, Tonn T, Steinbach JP, Wels WS. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. J Natl Cancer Inst 2016; 108(5): djv375

    Article  CAS  Google Scholar 

  129. Gao H, Li K, Tu H, Pan X, Jiang H, Shi B, Kong J, Wang H, Yang S, Gu J, Li Z. Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. Clin Cancer Res 2014; 20(24): 6418–6428

    Article  CAS  PubMed  Google Scholar 

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Yu, M., Li, Z. Natural killer cells in hepatocellular carcinoma: current status and perspectives for future immunotherapeutic approaches. Front. Med. 11, 509–521 (2017). https://doi.org/10.1007/s11684-017-0546-3

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