Hepatocellular carcinoma - From immunobiology to immunotherapy;Das hepatozellulre Karzinom - Von der Immunbiologie zur Immuntherapie

Zeitschrift fur Gastroenterologie

Volumn 50, Issue 1, 2012, Pages 47-56

  Flecken, T ^a   Schmidt, N ^a   Spangenberg, H C ^a   Thimme, R ^a  

^a UNIVERSITY OF FREIBURG   (Germany)

Author keywords

hepatitis B; hepatitis C; hepatocellular carcinoma; immune based therapy; liver; tumour immunology

Indexed keywords

IMMUNOMODULATING AGENT;

ARTICLE; CANCER INCIDENCE; CANCER SIZE; CHRONIC INFLAMMATION; HUMAN; IMMUNE RESPONSE; IMMUNOBIOLOGY; IMMUNOTHERAPY; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; BIOLOGICAL MODEL; IMMUNOLOGY; LIVER; LIVER TUMOR; REVIEW;

CARCINOMA, HEPATOCELLULAR; HUMANS; IMMUNOTHERAPY; LIVER; LIVER NEOPLASMS; MODELS, IMMUNOLOGICAL;

EID: 84855523406     PISSN: 00442771     EISSN: 14397803     Source Type: Journal    
DOI: 10.1055/s-0031-1282002     Document Type: Article

References (171)

1. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet: 1997; 349 1269 1276 (Pubitemid 27192468)
2. Ferlay J, Shin HR, Bray F et al. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France International Agency for Research on Cancer: 2010; http://globocan.iarc.fr [27/09/2011]
3. American Cancer Society Cancer Facts & Figures 2011. Atlanta American Cancer Society: 2011
4. El-Serag HB. Hepatocellular Carcinoma. New England Journal of Medicine: 2011; 365 1118 1127
5. El-Serag HB, Marrero JA, Rudolph L et al. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology: 2008; 134 1752 1763 (Pubitemid 351615415)
6. Talwalkar JA, Gores GJ. Diagnosis and staging of hepatocellular carcinoma. Gastroenterology: 2004; 127 126 132
7. Breuhahn K, Gores G, Schirmacher P. Strategies for hepatocellular carcinoma therapy and diagnostics: lessons learned from high throughput and profiling approaches. Hepatology: 2011; 53 2112 2121
8. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology: 2011; 53 1020 1022
9. Schmidt S, Follmann M, Malek N et al. Critical Appraisal of Clinical Practice Guidelines for Diagnosis and Treatment of Hepatocellular Carcinoma. J Gastroenterol Hepatol: 2011
10. Simonetti RG, Liberati A, Angiolini C et al. Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials. Ann Oncol: 1997; 8 117 136 (Pubitemid 27112878)
11. Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med: 2008; 359 378 390
12. Spangenberg HC, Thimme R, Blum HE. Targeted therapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol: 2009; 6 423 432
13. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer: 2006; 6 674 687 (Pubitemid 44286000)
14. Feo F, Frau M, Tomasi ML et al. Genetic and epigenetic control of molecular alterations in hepatocellular carcinoma. Exp Biol Med (Maywood): 2009; 234 726 736
15. Wong N, Lai P, Pang E et al. A comprehensive karyotypic study on human hepatocellular carcinoma by spectral karyotyping. Hepatology: 2000; 32 1060 1068
16. Kusano N, Okita K, Shirahashi H et al. Chromosomal imbalances detected by comparative genomic hybridization are associated with outcome of patients with hepatocellular carcinoma. Cancer: 2002; 94 746 751 (Pubitemid 34132304)
17. Totoki Y, Tatsuno K, Yamamoto S et al. High-resolution characterization of a hepatocellular carcinoma genome. Nat Genet: 2011; 43 464 469
18. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell: 2011; 144 646 674
19. Maass T, Sfakianakis I, Staib F et al. Microarray-based gene expression analysis of hepatocellular carcinoma. Curr Genomics: 2010; 11 261 268
20. Wilkens L, Flemming P, Gebel M et al. Induction of aneuploidy by increasing chromosomal instability during dedifferentiation of hepatocellular carcinoma. Proc Natl Acad Sci USA: 2004; 101 1309 1314 (Pubitemid 38182685)
21. Saeki A, Tamura S, Ito N et al. Frequent impairment of the spindle assembly checkpoint in hepatocellular carcinoma. Cancer: 2002; 94 2047 2054 (Pubitemid 34270059)
22. Urabe Y, Nouso K, Higashi T et al. Telomere length in human liver diseases. Liver: 1996; 16 293 297 (Pubitemid 26388119)
23. Plentz RR, Caselitz M, Bleck JS et al. Hepatocellular telomere shortening correlates with chromosomal instability and the development of human hepatoma. Hepatology: 2004; 40 80 86 (Pubitemid 38868926)
24. Shimojima M, Komine F, Hisatomi H et al. Detection of telomerase activity, telomerase RNA component, and telomerase reverse transcriptase in human hepatocellular carcinoma. Hepatol Res: 2004; 29 31 38 (Pubitemid 38594509)
25. Farazi PA, Glickman J, Jiang S et al. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma. Cancer Res: 2003; 63 5021 5027 (Pubitemid 37022640)
26. Minouchi K, Kaneko S, Kobayashi K. Mutation of p53 gene in regenerative nodules in cirrhotic liver. J Hepatol: 2002; 37 231 239 (Pubitemid 34833085)
27. Oda T, Tsuda H, Scarpa A et al. p53 gene mutation spectrum in hepatocellular carcinoma. Cancer Res: 1992; 52 6358 6364
28. Ueda H, Ullrich SJ, Gangemi JD et al. Functional inactivation but not structural mutation of p53 causes liver cancer. Nat Genet: 1995; 9 41 47
29. Deng L, Nagano-Fujii M, Tanaka M et al. NS3 protein of Hepatitis C virus associates with the tumour suppressor p53 and inhibits its function in an NS3 sequence-dependent manner. J Gen Virol: 2006; 87 1703 1713 (Pubitemid 43827226)
30. Lan KH, Sheu ML, Hwang SJ et al. HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis. Oncogene: 2002; 21 4801 4811
31. Ray RB, Steele R, Meyer K et al. Transcriptional repression of p53 promoter by hepatitis C virus core protein. J Biol Chem: 1997; 272 10983 10986 (Pubitemid 27184081)
32. Lee SG, Rho HM. Transcriptional repression of the human p53 gene by hepatitis B viral X protein. Oncogene: 2000; 19 468 471 (Pubitemid 30077349)
33. Wang XW, Forrester K, Yeh H et al. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci USA: 1994; 91 2230 2234 (Pubitemid 24092077)
34. Tokino T, Tamura H, Hori N et al. Chromosome deletions associated with hepatitis B virus integration. Virology: 1991; 185 879 882
35. Murakami Y, Saigo K, Takashima H et al. Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut: 2005; 54 1162 1168 (Pubitemid 41025914)
36. Hoek JB, Pastorino JG. Ethanol, oxidative stress, and cytokine-induced liver cell injury. Alcohol: 2002; 27 63 68 (Pubitemid 34626486)
37. Moriya K, Nakagawa K, Santa T et al. Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res: 2001; 61 4365 4370 (Pubitemid 32685760)
38. Molon B, Ugel S, Del Pozzo F et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med: 2011; 208 1949 1962
39. Whittaker S, Marais R, Zhu AX. The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene: 2010; 29 4989 5005
40. Ito Y, Takeda T, Sakon M et al. Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer: 2001; 84 1377 1383 (Pubitemid 32522107)
41. Jhappan C, Stahle C, Harkins RN et al. TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell: 1990; 61 1137 1146
42. Sandgren EP, Luetteke NC, Qiu TH et al. Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol Cell Biol: 1993; 13 320 330 (Pubitemid 23006909)
43. Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene: 2006; 25 3787 3800 (Pubitemid 43980474)
44. Daveau M, Scotte M, Francois A et al. Hepatocyte growth factor, transforming growth factor alpha, and their receptors as combined markers of prognosis in hepatocellular carcinoma. Mol Carcinog: 2003; 36 130 141 (Pubitemid 36314790)
45. Bangoura G, Liu ZS, Qian Q et al. Prognostic significance of HIF-2alpha/EPAS1 expression in hepatocellular carcinoma. World J Gastroenterol: 2007; 13 3176 3182 (Pubitemid 47064579)
46. Maass T, Thieringer FR, Mann A et al. Liver specific overexpression of platelet-derived growth factor-B accelerates liver cancer development in chemically induced liver carcinogenesis. Int J Cancer: 2011; 128 1259 1268
47. Mas VR, Maluf DG, Archer KJ et al. Angiogenesis soluble factors as hepatocellular carcinoma noninvasive markers for monitoring hepatitis C virus cirrhotic patients awaiting liver transplantation. Transplantation: 2007; 84 1262 1271 (Pubitemid 351339314)
48. Yamamoto A, Dhar DK, El-Assal ON et al. Thymidine phosphorylase (platelet-derived endothelial cell growth factor), microvessel density and clinical outcome in hepatocellular carcinoma. J Hepatol: 1998; 29 290 299 (Pubitemid 28352815)
49. El-Assal ON, Yamanoi A, Soda Y et al. Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology: 1998; 27 1554 1562 (Pubitemid 28264678)
50. Hwang YH, Choi JY, Kim S et al. Over-expression of c-raf-1 proto-oncogene in liver cirrhosis and hepatocellular carcinoma. Hepatol Res: 2004; 29 113 121 (Pubitemid 38667508)
51. Hu TH, Huang CC, Lin PR et al. Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/MMAC1/TEP1#x200A;TEP1 in hepatocellular carcinoma. Cancer: 2003; 97 1929 1940
52. Wong CM, Fan ST, Ng IO. beta-Catenin mutation and overexpression inhepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer: 2001; 92 136 145 (Pubitemid 32623050)
53. de La Coste A, Romagnolo B, Billuart P et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA: 1998; 95 8847 8851 (Pubitemid 28350577)
54. Erhardt A, Hassan M, Heintges T et al. Hepatitis C virus core protein induces cell proliferation and activates ERK, JNK, and p38 MAP kinases together with the MAP kinase phosphatase MKP-1 in a HepG2 Tet-Off cell line. Virology: 2002; 292 272 284 (Pubitemid 34920547)
55. Feitelson MA, Reis HM, Tufan NL et al. Putative roles of hepatitis Bxantigen in the pathogenesis of chronic liver disease. Cancer Lett: 2009; 286 69 79
56. Fukutomi T, Zhou Y, Kawai S et al. Hepatitis C virus core protein stimulates hepatocyte growth: correlation with upregulation of wnt-1 expression. Hepatology: 2005; 41 1096 1105 (Pubitemid 40593917)
57. He Y, Nakao H, Tan SL et al. Subversion of cell signaling pathways by hepatitis C virus nonstructural 5A protein via interaction with Grb2 and P85 phosphatidylinositol 3-kinase. J Virol: 2002; 76 9207 9217 (Pubitemid 34919879)
58. Huang S, He X. The role of microRNAs in liver cancer progression. Br J Cancer: 2011; 104 235 240
59. Law PT, Wong N. Emerging roles of microRNA in the intracellular signaling networks of hepatocellular carcinoma. J Gastroenterol Hepatol: 2011; 26 437 449
60. Meng F, Henson R, Wehbe-Janek H et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology: 2007; 133 647 658 (Pubitemid 47187346)
61. Liu S, Guo W, Shi J et al. MicroRNA-135a Contributes to the Development of Portal Vein Tumor Thrombus by Promoting Metastasis in Hepatocellular Carcinoma. J Hepatol: 2011
62. Herath NI, Leggett BA, MacDonald GA. Review of genetic and epigenetic alterations in hepatocarcinogenesis. J Gastroenterol Hepatol: 2006; 21 15 21
63. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet: 2002; 31 339 346 (Pubitemid 35154440)
64. Goeppert B, Schmezer P, Dutruel C et al. Down-regulation of tumor suppressor A kinase anchor protein 12 in human hepatocarcinogenesis by epigenetic mechanisms. Hepatology: 2010; 52 2023 2033
65. Villanueva A, Hoshida Y, Battiston C et al. Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma. Gastroenterology: 2011; 140 1501 1512 e1502
66. Woo HG, Park ES, Thorgeirsson SS et al. Exploring genomic profiles of hepatocellular carcinoma. Mol Carcinog: 2011; 50 235 243
67. Chenivesse X, Franco D, Brechot C. MDR1 (multidrug resistance) gene expression in human primary liver cancer and cirrhosis. J Hepatol: 1993; 18 168 172 (Pubitemid 23246943)
68. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology: 2008; 48 1312 1327
69. Flecken T, Spangenberg HC, Thimme R. Immunobiology of hepatocellular carcinoma. Langenbecks Arch Surg: 2011
70. Nakamoto Y, Guidotti LG, Kuhlen CV et al. Immune pathogenesis of hepatocellular carcinoma. J Exp Med: 1998; 188 341 350 (Pubitemid 28357762)
71. Haybaeck J, Zeller N, Wolf MJ et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell: 2009; 16 295 308
72. Tanaka J, Sugimoto K, Shiraki K et al. Functional cell surface expression of toll-like receptor 9 promotes cell proliferation and survival in human hepatocellular carcinomas. Int J Oncol: 2010; 37 805 814
73. He G, Karin M. NF-kappaB and STAT3 key players in liver inflammation and cancer. Cell Res: 2011; 21 159 168
74. Sakurai T, He G, Matsuzawa A et al. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell: 2008; 14 156 165
75. Maeda S, Chang L, Li ZW et al. IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity: 2003; 19 725 737 (Pubitemid 37490797)
76. Luedde T, Beraza N, Kotsikoris V et al. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell: 2007; 11 119 132 (Pubitemid 46209851)
77. Pham CG, Bubici C, Zazzeroni F et al. Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell: 2004; 119 529 542 (Pubitemid 39482352)
78. Maeda S, Kamata H, Luo JL et al. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell: 2005; 121 977 990 (Pubitemid 40884391)
79. He G, Yu GY, Temkin V et al. Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell: 2010; 17 286 297
80. Al ZaidSiddiquee K, Turkson J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res: 2008; 18 254 267 (Pubitemid 351206162)
81. Calvisi DF, Ladu S, Gorden A et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology: 2006; 130 1117 1128
82. Wong VW, Yu J, Cheng AS et al. High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B. Int J Cancer: 2009; 124 2766 2770
83. Naugler WE, Sakurai T, Kim S et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science: 2007; 317 121 124 (Pubitemid 47056470)
84. Nakagawa H, Maeda S, Yoshida H et al. Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: an analysis based on gender differences. Int J Cancer: 2009; 125 2264 2269
85. Achyut BR, Yang L. Transforming Growth Factor-beta in the Gastrointestinal and Hepatic Tumor Microenvironment. Gastroenterology: 2011
86. Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol: 2010; 40 1830 1835
87. Weaver CT, Harrington LE, Mangan PR et al. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity: 2006; 24 677 688 (Pubitemid 43867371)
88. Kuang DM, Peng C, Zhao Q et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology: 2010; 51 154 164
89. Kuang DM, Peng C, Zhao Q et al. Tumor-activated monocytes promote expansion of IL-17-producing CD8+ T cells in hepatocellular carcinoma patients. J Immunol: 2010; 185 1544 1549
90. Jiang R, Tan Z, Deng L et al. Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology: 2011
91. Park O, Wang H, Weng H et al. In vivo consequences of liver-specific interleukin-22 expression in mice: Implications for human liver disease progression. Hepatology: 2011; 54 252 261
92. Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity: 2004; 21 467 476 (Pubitemid 39370503)
93. Kuang DM, Zhao Q, Wu Y et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol: 2011; 54 948 955
94. Zhang JP, Yan J, Xu J et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol: 2009; 50 980 989
95. Li YW, Qiu SJ, Fan J et al. Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J Hepatol: 2011; 54 497 505
96. Budhu A, Wang XW. The role of cytokines in hepatocellular carcinoma. JLeukoc Biol: 2006; 80 1197 1213 (Pubitemid 44904957)
97. Ho SY, Wang YJ, Chen HL et al. Increased risk of developing hepatocellular carcinoma associated with carriage of the TNF2 allele of the -308 tumor necrosis factor-alpha promoter gene. Cancer Causes Control: 2004; 15 657 663
98. Wada Y, Nakashima O, Kutami R et al. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology: 1998; 27 407 414 (Pubitemid 28081054)
99. Gao Q, Qiu SJ, Fan J et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol: 2007; 25 2586 2593 (Pubitemid 47041232)
100. Unitt E, Marshall A, Gelson W et al. Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J Hepatol: 2006; 45 246 253
101. Ikeguchi M, Oi K, Hirooka Y et al. CD8+ lymphocyte infiltration and apoptosis in hepatocellular carcinoma. Eur J Surg Oncol: 2004; 30 53 57 (Pubitemid 38180992)
102. Hiroishi K, Eguchi J, Baba T et al. Strong CD8(+) T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma. J Gastroenterol: 2010; 45 451 458
103. Yoong KF, McNab G, Hubscher SG et al. Vascular adhesion protein-1 and ICAM-1 support the adhesion of tumor-infiltrating lymphocytes to tumor endothelium in human hepatocellular carcinoma. J Immunol: 1998; 160 3978 3988 (Pubitemid 28176106)
104. Fisher DT, Chen Q, Skitzki JJ et al. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J Clin Invest: 2011; 121 3846 3859
105. Finn OJ. Cancer immunology. N Engl J Med: 2008; 358 2704 2715
106. Breous E, Thimme R. Potential of immunotherapy for hepatocellular carcinoma. J Hepatol: 2011; 54 830 834
107. Mizukoshi E, Nakamoto Y, Arai K et al. Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma. Hepatology: 2011; 53 1206 1216
108. Mizukoshi E, Nakamoto Y, Marukawa Y et al. Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma. Hepatology: 2006; 43 1284 1294 (Pubitemid 43980107)
109. Gehring AJ, Ho ZZ, Tan AT et al. Profile of tumor antigen-specific CD8 Tcells in patients with hepatitis B virus-related hepatocellular carcinoma. Gastroenterology: 2009; 137 682 690
110. Zerbini A, Pilli M, Soliani P et al. Ex vivo characterization of tumor-derived melanoma antigen encoding gene-specific CD8+cells in patients with hepatocellular carcinoma. J Hepatol: 2004; 40 102 109 (Pubitemid 38064718)
111. Butterfield LH, Ribas A, Meng WS et al. T-cell responses to HLA-A*0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer. Clin Cancer Res: 2003; 9 5902 5908 (Pubitemid 38018074)
112. Thimme R, Neagu M, Boettler T et al. Comprehensive analysis of the alpha-fetoprotein-specific CD8+ T cell responses in patients with hepatocellular carcinoma. Hepatology: 2008; 48 1821 1833
113. Komori H, Nakatsura T, Senju S et al. Identification of HLA-A2- or HLA-A24-restricted CTL epitopes possibly useful for glypican-3-specific immunotherapy of hepatocellular carcinoma. Clin Cancer Res: 2006; 12 2689 2697
114. Evdokimova VN, Liu Y, Potter DM et al. AFP-specific CD4+ helper T-cell responses in healthy donors and HCC patients. J Immunother: 2007; 30 425 437 (Pubitemid 46684432)
115. Witkowski M, Spangenberg HC, Neumann-Haefelin C et al. Lack of ex vivo peripheral and intrahepatic alpha-fetoprotein-specific CD4+ responses in hepatocellular carcinoma. Int J Cancer: 2010
116. Ayaru L, Pereira SP, Alisa A et al. Unmasking of alpha-fetoprotein- specific CD4(+) T cell responses in hepatocellular carcinoma patients undergoing embolization. J Immunol: 2007; 178 1914 1922 (Pubitemid 46154664)
117. Zerbini A, Pilli M, Penna A et al. Radiofrequency thermal ablation of hepatocellular carcinoma liver nodules can activate and enhance tumor-specific T-cell responses. Cancer Res: 2006; 66 1139 1146 (Pubitemid 43165983)
118. Cai XY, Gao Q, Qiu SJ et al. Dendritic cell infiltration and prognosis of human hepatocellular carcinoma. J Cancer Res Clin Oncol: 2006; 132 293 301
119. Caligiuri MA. Human natural killer cells. Blood: 2008; 112 461 469
120. 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
121. Taketomi A, Shimada M, Shirabe K et al. Natural killer cell activity in patients with hepatocellular carcinoma: a new prognostic indicator after hepatectomy. Cancer: 1998; 83 58 63 (Pubitemid 28299629)
122. Zerbini A, Pilli M, Laccabue D et al. Radiofrequency thermal ablation for hepatocellular carcinoma stimulates autologous NK-cell response. Gastroenterology: 2010; 138 1931 1942
123. Nakano K, Orita T, Nezu J et al. Anti-glypican 3 antibodies cause ADCC against human hepatocellular carcinoma cells. Biochem Biophys Res Commun: 2009; 378 279 284
124. Chen X, Fu S, Chen F et al. Identification of tumor-associated antigens in human hepatocellular carcinoma by autoantibodies. Oncol Rep: 2008; 20 979 985
125. Heo CK, Woo MK, Yu DY et al. Identification of autoantibody against fatty acid synthase in hepatocellular carcinoma mouse model and its application to diagnosis of HCC. Int J Oncol: 2010; 36 1453 1459
126. Huang J, Cai MY, Wei DP. HLA class I expression in primary hepatocellular carcinoma. World J Gastroenterol: 2002; 8 654 657 (Pubitemid 34918658)
127. Wherry EJ. T cell exhaustion. Nat Immunol: 2011; 12 492 499
128. Zhao Q, Xiao X, Wu Y et al. Interleukin-17-educated monocytes suppress cytotoxic T-cell function through B7-H1 in hepatocellular carcinoma patients. Eur J Immunol: 2011; 41 2314 2322
129. Wu K, Kryczek I, Chen L et al. Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res: 2009; 69 8067 8075
130. Gao Q, Wang XY, Qiu SJ et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res: 2009; 15 971 979
131. Maki A, Matsuda M, Asakawa M et al. Decreased expression of CD28 coincides with the down-modulation of CD3zeta and augmentation of caspase-3 activity in T cells from hepatocellular carcinoma-bearing patients and hepatitis C virus-infected patients. J Gastroenterol Hepatol: 2004; 19 1348 1356 (Pubitemid 40052852)
132. Hsu PN, Yang TC, Kao JT et al. Increased PD-1 and decreased CD28 expression in chronic hepatitis B patients with advanced hepatocellular carcinoma. Liver Int: 2010; 30 1379 1386
133. Shi F, Shi M, Zeng Z et al. PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer: 2011; 128 887 896
134. Appay V, van Lier RA, Sallusto F et al. Phenotype and function of human T lymphocyte subsets: consensus and issues. Cytometry A: 2008; 73 975 983
135. Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol: 2010; 10 753 766
136. Ormandy LA, Farber A, Cantz T et al. Direct ex vivo analysis of dendritic cells in patients with hepatocellular carcinoma. World J Gastroenterol: 2006; 12 3275 3282 (Pubitemid 43881355)
137. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity: 2009; 30 636 645
138. Ormandy LA, Hillemann T, Wedemeyer H et al. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res: 2005; 65 2457 2464 (Pubitemid 40490158)
139. Yang XH, Yamagiwa S, Ichida T et al. Increase of CD4+ CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma. J Hepatol: 2006; 45 254 262
140. Fu J, Xu D, Liu Z et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology: 2007; 132 2328 2339 (Pubitemid 46890865)
141. Unitt E, Rushbrook SM, Marshall A et al. Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology: 2005; 41 722 730 (Pubitemid 40462933)
142. Zhou J, Ding T, Pan W et al. Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. Int J Cancer: 2009; 125 1640 1648
143. Cao M, Cabrera R, Xu Y et al. Hepatocellular carcinoma cell supernatants increase expansion and function of CD4(+)CD25(+) regulatory T cells. Lab Invest: 2007; 87 582 590 (Pubitemid 46788787)
144. Chen KJ, Lin SZ, Zhou L et al. Selective Recruitment of Regulatory T Cell through CCR6-CCL20 in Hepatocellular Carcinoma Fosters Tumor Progression and Predicts Poor Prognosis. PLoS One: 2011; 6 e24671
145. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol: 2009; 182 4499 4506
146. Hoechst B, Voigtlaender T, Ormandy L et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology: 2009; 50 799 807
147. Hu CE, Gan J, Zhang RD et al. Up-regulated myeloid-derived suppressor cell contributes to hepatocellular carcinoma development by impairing dendritic cell function. Scand J Gastroenterol: 2011; 46 156 164
148. Hoechst B, Ormandy LA, Ballmaier M et al. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology: 2008; 135 234 243 (Pubitemid 351899008)
149. Kohga K, Takehara T, Tatsumi T et al. Anticancer chemotherapy inhibits MHC class I-related chain a ectodomain shedding by downregulating ADAM10 expression in hepatocellular carcinoma. Cancer Res: 2009; 69 8050 8057
150. Kohga K, Takehara T, Tatsumi T et al. 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 1264 1273
151. Kumar V, Kato N, Urabe Y et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet: 2011; 43 455 458
152. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science: 2011; 331 1565 1570
153. Avella DM, Li G, Schell TD et al. Regression of established hepatocellular carcinoma is induced by chemo-immunotherapy in an orthotopic murine model. Hepatology: 2011
154. Grimm CF, Ortmann D, Mohr L et al. Mouse alpha-fetoprotein-specific DNA-based immunotherapy of hepatocellular carcinoma leads to tumor regression in mice. Gastroenterology: 2000; 119 1104 1112
155. Cany J, Barteau B, Tran L et al. AFP-specific immunotherapy impairs growth of autochthonous hepatocellular carcinoma in mice. J Hepatol: 2011; 54 115 121
156. Gonzalez-Carmona MA, Lukacs-Kornek V, Timmerman A et al. CD40ligand-expressing dendritic cells induce regression of hepatocellular carcinoma by activating innate and acquired immunity in vivo. Hepatology: 2008; 48 157 168 (Pubitemid 351975540)
157. Kayashima H, Toshima T, Okano S et al. Intratumoral neoadjuvant immunotherapy using IL-12 and dendritic cells is an effective strategy to control recurrence of murine hepatocellular carcinoma in immunosuppressed mice. J Immunol: 2010; 185 698 708
158. Boozari B, Mundt B, Woller N et al. Antitumoural immunity by virus-mediated immunogenic apoptosis inhibits metastatic growth of hepatocellular carcinoma. Gut: 2010; 59 1416 1426
159. Reinisch W, Holub M, Katz A et al. Prospective pilot study of recombinant granulocyte-macrophage colony-stimulating factor and interferon-gamma in patients with inoperable hepatocellular carcinoma. J Immunother: 2002; 25 489 499 (Pubitemid 35266314)
160. Palmer DH, Midgley RS, Mirza N et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology: 2009; 49 124 132
161. Butterfield LH, Ribas A, Dissette VB et al. A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res: 2006; 12 2817 2825
162. Greten TF, Forner A, Korangy F et al. A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma. BMC Cancer: 2010; 10 209
163. Yoshikawa T, Nakatsugawa M, Suzuki S et al. HLA-A2-restricted glypican-3 peptide-specific CTL clones induced by peptide vaccine show high avidity and antigen-specific killing activity against tumor cells. Cancer Sci: 2011; 102 918 925
164. Takayama T, Sekine T, Makuuchi M et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet: 2000; 356 802 807
165. Kuang M, Peng BG, Lu MD et al. Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma. Clin Cancer Res: 2004; 10 1574 1579 (Pubitemid 38435545)
166. Couzin-Frankel J. Immune therapy steps up the attack. Science: 2010; 330 440 443
167. Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med: 2010; 363 711 723
168. Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med: 2010; 363 411 422
169. Schwartzentruber DJ, Lawson DH, Richards JM et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med: 2011; 364 2119 2127
170. Becker N, Wahrendorf J. Krebsatlas der Bundesrepublik Deutschland 19811990. Springer: 1998; www.krebsatlas.de [12/10/2011]
171. Bevlkerung nach dem Gebietsstand. Statistisches Bundesamt: 2011; www.destatis.de [12/10/2011]