PDF herunterladen
Semin Liver Dis 2020; 40(02): 131-142
DOI: 10.1055/s-0039-3399534
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Impact of Viral Etiologies on the Development of Novel Immunotherapy for Hepatocellular Carcinoma

Chun Jye Lim
1   Translational Immunology Institute (TII), SingHealth-Duke-NUS Academic Medical Centre, Singapore, Singapore
,
Valerie Chew
1   Translational Immunology Institute (TII), SingHealth-Duke-NUS Academic Medical Centre, Singapore, Singapore
› Institutsangaben Funding This work was supported by the National Medical Research Council (NMRC), Singapore (ref numbers: TCR15Jun006, CIRG16may048, CSAS16Nov006, CSASI17may003, and LCG17MAY003).
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
06. Dezember 2019 (online)

   Lizenzen und Reprints

Abstract

Hepatocellular carcinoma (HCC), is the most common type of liver cancer which is derived mostly from the background of chronic inflammation. Chronic hepatitis viral infection remains one of the most common etiologies implicated in chronic liver inflammation, cirrhosis, and HCC. With such background inflammation, immunotherapy—particularly the checkpoint inhibitors—have been tested in HCC patients with unprecedented success. However, despite the initial enthusiasm, the response rate to immunotherapy remains modest in most clinical trials (approximately 20%), with mixed reports on response rates in hepatitis viral-related HCC as compared with nonviral HCC. Given such complexity in response to immunotherapy, it is increasingly appreciated that deeper understanding of the tumor molecular features and tumor microenvironment of hepatitis viral-related HCC is crucial for the design of more effective immunotherapeutics. We discuss herein the current knowledge in tumor genomic mutational and immune landscapes as well as the ongoing immunotherapy trials in HCC with the unique focus on their viral etiologies. Based on this understanding, we also outline perspectives and rationale on the design of potential immunotherapeutic strategies in HCC patients according to their viral etiologies.

Keywords

hepatitis virus infection - hepatocellular carcinoma - immunotherapy - tumor microenvironment - viral-related HCC
 

  • References

  • 1 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (06) 394-424
    CrossrefPubMedGoogle Scholar
  • 2 El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012; 142 (06) 1264-1273.e1
    CrossrefPubMedGoogle Scholar
  • 3 Abbas Z, Abbas M, Abbas S, Shazi L. Hepatitis D and hepatocellular carcinoma. World J Hepatol 2015; 7 (05) 777-786
    CrossrefPubMedGoogle Scholar
  • 4 Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer 2014; 14 (02) 135-146
    CrossrefPubMedGoogle Scholar
  • 5 Schinzari V, Barnaba V, Piconese S. Chronic hepatitis B virus and hepatitis C virus infections and cancer: synergy between viral and host factors. Clin Microbiol Infect 2015; 21 (11) 969-974
    CrossrefPubMedGoogle Scholar
  • 6 Liang TJ. Hepatitis B: the virus and disease. Hepatology 2009; 49 (5, Suppl): S13-S21
    CrossrefPubMedGoogle Scholar
  • 7 Ringelhan M, Protzer U. Oncogenic potential of hepatitis B virus encoded proteins. Curr Opin Virol 2015; 14: 109-115
    CrossrefPubMedGoogle Scholar
  • 8 Simonetti J, Bulkow L, McMahon BJ. , et al. Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus. Hepatology 2010; 51 (05) 1531-1537
    CrossrefPubMedGoogle Scholar
  • 9 Livingston SE, Simonetti JP, Bulkow LR. , et al. Clearance of hepatitis B antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology 2007; 133 (05) 1452-1457
    CrossrefPubMedGoogle Scholar
  • 10 Chiu YT, Wong JK, Choi SW. , et al. Novel pre-mRNA splicing of intronically integrated HBV generates oncogenic chimera in hepatocellular carcinoma. J Hepatol 2016; 64 (06) 1256-1264
    CrossrefPubMedGoogle Scholar
  • 11 Furuta M, Tanaka H, Shiraishi Y. , et al. Characterization of HBV integration patterns and timing in liver cancer and HBV-infected livers. Oncotarget 2018; 9 (38) 25075-25088
    CrossrefPubMedGoogle Scholar
  • 12 Qasim W, Brunetto M, Gehring AJ. , et al. Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient. J Hepatol 2015; 62 (02) 486-491
    CrossrefPubMedGoogle Scholar
  • 13 Tan AT, Yang N, Lee Krishnamoorthy T. , et al. Use of expression profiles of HBV-DNA integrated into genomes of hepatocellular carcinoma cells to select T cells for immunotherapy. Gastroenterology 2019; 156 (06) 1862-1876.e9
    CrossrefPubMedGoogle Scholar
  • 14 Li HC, Lo SY. Hepatitis C virus: virology, diagnosis and treatment. World J Hepatol 2015; 7 (10) 1377-1389
    CrossrefPubMedGoogle Scholar
  • 15 Stoll-Keller F, Barth H, Fafi-Kremer S, Zeisel MB, Baumert TF. Development of hepatitis C virus vaccines: challenges and progress. Expert Rev Vaccines 2009; 8 (03) 333-345
    CrossrefPubMedGoogle Scholar
  • 16 Friedman RM, Contente S. Treatment of hepatitis C infections with interferon: a historical perspective. Hepat Res Treat 2010; 2010: 323926
    PubMedGoogle Scholar
  • 17 Majumdar A, Kitson MT, Roberts SK. Systematic review: current concepts and challenges for the direct-acting antiviral era in hepatitis C cirrhosis. Aliment Pharmacol Ther 2016; 43 (12) 1276-1292
    CrossrefPubMedGoogle Scholar
  • 18 Chung RT, Baumert TF. Curing chronic hepatitis C—the arc of a medical triumph. N Engl J Med 2014; 370 (17) 1576-1578
    CrossrefPubMedGoogle Scholar
  • 19 Cabibbo G, Celsa C, Cammà C, Craxì A. Should we cure hepatitis C virus in patients with hepatocellular carcinoma while treating cancer?. Liver Int 2018; 38 (12) 2108-2116
    CrossrefPubMedGoogle Scholar
  • 20 Reig M, Mariño Z, Perelló C. , et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016; 65 (04) 719-726
    CrossrefPubMedGoogle Scholar
  • 21 Conti F, Buonfiglioli F, Scuteri A. , et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol 2016; 65 (04) 727-733
    CrossrefPubMedGoogle Scholar
  • 22 Kozbial K, Moser S, Schwarzer R. , et al. Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with sustained virologic response following interferon-free direct-acting antiviral treatment. J Hepatol 2016; 65 (04) 856-858
    CrossrefPubMedGoogle Scholar
  • 23 Maan R, Feld JJ. Risk for hepatocellular carcinoma after hepatitis C virus antiviral therapy with direct-acting antivirals: case closed?. Gastroenterology 2017; 153 (04) 890-892
    CrossrefPubMedGoogle Scholar
  • 24 Sung WK, Zheng H, Li S. , et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet 2012; 44 (07) 765-769
    CrossrefPubMedGoogle Scholar
  • 25 Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu; Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 2017; 169: 1327-1341
    CrossrefPubMedGoogle Scholar
  • 26 Hoshida Y, Villanueva A, Sangiovanni A. , et al. Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis. Gastroenterology 2013; 144 (05) 1024-1030
    CrossrefPubMedGoogle Scholar
  • 27 Abu Dayyeh BK, Yang M, Fuchs BC. , et al; HALT-C Trial Group. A functional polymorphism in the epidermal growth factor gene is associated with risk for hepatocellular carcinoma. Gastroenterology 2011; 141 (01) 141-149
    CrossrefPubMedGoogle Scholar
  • 28 Wang Y, Kato N, Hoshida Y. , et al. Interleukin-1beta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection. Hepatology 2003; 37 (01) 65-71
    CrossrefPubMedGoogle Scholar
  • 29 Zong L, Peng H, Sun C. , et al. Breakdown of adaptive immunotolerance induces hepatocellular carcinoma in HBsAg-tg mice. Nat Commun 2019; 10 (01) 221
    CrossrefPubMedGoogle Scholar
  • 30 Rehermann B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat Med 2013; 19 (07) 859-868
    CrossrefPubMedGoogle Scholar
  • 31 Shimizu Y. T cell immunopathogenesis and immunotherapeutic strategies for chronic hepatitis B virus infection. World J Gastroenterol 2012; 18 (20) 2443-2451
    CrossrefPubMedGoogle Scholar
  • 32 Schuch A, Hoh A, Thimme R. The role of natural killer cells and CD8(+) T cells in hepatitis B virus infection. Front Immunol 2014; 5: 258
    PubMedGoogle Scholar
  • 33 Hu L, Zhai X, Liu J. , et al. Genetic variants in human leukocyte antigen/DP-DQ influence both hepatitis B virus clearance and hepatocellular carcinoma development. Hepatology 2012; 55 (05) 1426-1431
    CrossrefPubMedGoogle Scholar
  • 34 Tong HV, Toan NL, Song LH, Bock CT, Kremsner PG, Velavan TP. Hepatitis B virus-induced hepatocellular carcinoma: functional roles of MICA variants. J Viral Hepat 2013; 20 (10) 687-698
    CrossrefPubMedGoogle Scholar
  • 35 Gu X, Qi P, Zhou F. , et al. +49G > A polymorphism in the cytotoxic T-lymphocyte antigen-4 gene increases susceptibility to hepatitis B-related hepatocellular carcinoma in a male Chinese population. Hum Immunol 2010; 71 (01) 83-87
    CrossrefPubMedGoogle Scholar
  • 36 Tang S, Yuan Y, He Y. , et al. Genetic polymorphism of interleukin-6 influences susceptibility to HBV-related hepatocellular carcinoma in a male Chinese Han population. Hum Immunol 2014; 75 (04) 297-301
    CrossrefPubMedGoogle Scholar
  • 37 Hoshida Y, Fuchs BC, Bardeesy N, Baumert TF, Chung RT. Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma. J Hepatol 2014; 61 (1, Suppl): S79-S90
    CrossrefPubMedGoogle Scholar
  • 38 Kumar V, Kato N, Urabe Y. , et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet 2011; 43 (05) 455-458
    CrossrefPubMedGoogle Scholar
  • 39 Bauer S, Groh V, Wu J. , et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999; 285 (5428): 727-729
    CrossrefPubMedGoogle Scholar
  • 40 Yarchoan M, Xing D, Luan L. , et al. Characterization of the immune microenvironment in hepatocellular carcinoma. Clin Cancer Res 2017; 23 (23) 7333-7339
    CrossrefPubMedGoogle Scholar
  • 41 Goodman AM, Kato S, Bazhenova L. , et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther 2017; 16 (11) 2598-2608
    CrossrefPubMedGoogle Scholar
  • 42 Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 2017; 377 (25) 2500-2501
    CrossrefPubMedGoogle Scholar
  • 43 Ahn SM, Jang SJ, Shim JH. , et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology 2014; 60 (06) 1972-1982
    CrossrefPubMedGoogle Scholar
  • 44 El-Khoueiry AB, Sangro B, Yau T. , et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017; 389 (10088): 2492-2502
    CrossrefPubMedGoogle Scholar
  • 45 Goossens N, Sun X, Hoshida Y. Molecular classification of hepatocellular carcinoma: potential therapeutic implications. Hepat Oncol 2015; 2 (04) 371-379
    PubMedGoogle Scholar
  • 46 Zhai W, Lim TK, Zhang T. , et al. The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma. Nat Commun 2017; 8: 4565
    CrossrefPubMedGoogle Scholar
  • 47 Chew V, Chen J, Lee D. , et al. Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma. Gut 2012; 61 (03) 427-438
    CrossrefPubMedGoogle Scholar
  • 48 Chew V, Lai L, Pan L. , et al. Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses. Proc Natl Acad Sci U S A 2017; 114 (29) E5900-E5909
    CrossrefPubMedGoogle Scholar
  • 49 Nishida N, Kudo M. Immunological microenvironment of hepatocellular carcinoma and its clinical implication. Oncology 2017; 92 (Suppl. 01) 40-49
    CrossrefPubMedGoogle Scholar
  • 50 Yang P, Markowitz GJ, Wang XF. The hepatitis B virus-associated tumor microenvironment in hepatocellular carcinoma. Natl Sci Rev 2014; 1 (03) 396-412
    PubMedGoogle Scholar
  • 51 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 (07) 2328-2339
    CrossrefPubMedGoogle Scholar
  • 52 Stoop JN, van der Molen RG, Baan CC. , et al. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology 2005; 41 (04) 771-778
    CrossrefPubMedGoogle Scholar
  • 53 Yang P, Li QJ, Feng Y. , et al. TGF-β-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell 2012; 22 (03) 291-303
    CrossrefPubMedGoogle Scholar
  • 54 Ye B, Liu X, Li X, Kong H, Tian L, Chen Y. T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance. Cell Death Dis 2015; 6: e1694
    CrossrefPubMedGoogle Scholar
  • 55 Li H, Wu K, Tao K. , et al. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 2012; 56 (04) 1342-1351
    CrossrefPubMedGoogle Scholar
  • 56 Li FJ, Zhang Y, Jin GX, Yao L, Wu DQ. Expression of LAG-3 is coincident with the impaired effector function of HBV-specific CD8(+) T cell in HCC patients. Immunol Lett 2013; 150 (1-2): 116-122
    CrossrefPubMedGoogle Scholar
  • 57 Nakamoto N, Cho H, Shaked A. , et al. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog 2009; 5 (02) e1000313
    CrossrefPubMedGoogle Scholar
  • 58 Nakamoto N, Kaplan DE, Coleclough J. , et al. Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization. Gastroenterology 2008; 134 (07) 1927-1937 , 1937.e1–1937.e2
    CrossrefPubMedGoogle Scholar
  • 59 Piconese S, Timperi E, Pacella I. , et al. Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue. Hepatology 2014; 60 (05) 1494-1507
    CrossrefPubMedGoogle Scholar
  • 60 Liu P, Chen L, Zhang H. Natural killer cells in liver disease and hepatocellular carcinoma and the NK cell-based immunotherapy. J Immunol Res 2018; 2018: 1206737
    PubMedGoogle Scholar
  • 61 Oliviero B, Varchetta S, Paudice E. , et al. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 2009; 137 (03) 1151-1160 , 1160.e1–1160.e7
    CrossrefPubMedGoogle Scholar
  • 62 Sun C, Sun HY, Xiao WH, Zhang C, Tian ZG. Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy. Acta Pharmacol Sin 2015; 36 (10) 1191-1199
    CrossrefPubMedGoogle Scholar
  • 63 Boltjes A, Movita D, Boonstra A, Woltman AM. The role of Kupffer cells in hepatitis B and hepatitis C virus infections. J Hepatol 2014; 61 (03) 660-671
    CrossrefPubMedGoogle Scholar
  • 64 Maeda S, Kamata H, Luo JL, Leffert H, Karin M. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 2005; 121 (07) 977-990
    CrossrefPubMedGoogle Scholar
  • 65 Hagen TM, Huang S, Curnutte J. , et al. Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma. Proc Natl Acad Sci U S A 1994; 91 (26) 12808-12812
    CrossrefPubMedGoogle Scholar
  • 66 Yu LX, Ling Y, Wang HY. Role of nonresolving inflammation in hepatocellular carcinoma development and progression. NPJ Precis Oncol 2018; 2 (01) 6
    PubMedGoogle Scholar
  • 67 Yeung OW, Lo CM, Ling CC. , et al. Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. J Hepatol 2015; 62 (03) 607-616
    CrossrefPubMedGoogle Scholar
  • 68 Kuang DM, Zhao Q, Peng C. , et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med 2009; 206 (06) 1327-1337
    CrossrefPubMedGoogle Scholar
  • 69 Lim CJ, Lee YH, Pan L. , et al. Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. Gut 2019; 68 (05) 916-927
    CrossrefPubMedGoogle Scholar
  • 70 Aalaei-Andabili SH, Alavian SM. Regulatory T cells are the most important determinant factor of hepatitis B infection prognosis: a systematic review and meta-analysis. Vaccine 2012; 30 (38) 5595-5602
    CrossrefPubMedGoogle Scholar
  • 71 Pallett LJ, Davies J, Colbeck EJ. , et al. IL-2 high tissue-resident T cells in the human liver: sentinels for hepatotropic infection. J Exp Med 2017; 214 (06) 1567-1580
    CrossrefPubMedGoogle Scholar
  • 72 Sun C, Fu B, Gao Y. , et al. TGF-β1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence. PLoS Pathog 2012; 8 (03) e1002594
    CrossrefPubMedGoogle Scholar
  • 73 Zhu AX, Finn RS, Edeline J. , et al; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 2018; 19 (07) 940-952
    CrossrefPubMedGoogle Scholar
  • 74 Hoseini SS, Cheung NV. Immunotherapy of hepatocellular carcinoma using chimeric antigen receptors and bispecific antibodies. Cancer Lett 2017; 399: 44-52
    CrossrefPubMedGoogle Scholar
  • 75 Gehring AJ, Ho ZZ, Tan AT. , et al. Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma. Gastroenterology 2009; 137 (02) 682-690
    CrossrefPubMedGoogle Scholar
  • 76 Fu S, Li N, Zhou PC, Huang Y, Zhou RR, Fan XG. Detection of HBV DNA and antigens in HBsAg-positive patients with primary hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2017; 41 (04) 415-423
    CrossrefPubMedGoogle Scholar
  • 77 Wang Y, Wu MC, Sham JS. , et al. Different expression of hepatitis B surface antigen between hepatocellular carcinoma and its surrounding liver tissue, studied using a tissue microarray. J Pathol 2002; 197 (05) 610-616
    CrossrefPubMedGoogle Scholar
  • 78 Vandepapelière P, Lau GK, Leroux-Roels G. , et al; Therapeutic HBV Vaccine Group of Investigators. Therapeutic vaccination of chronic hepatitis B patients with virus suppression by antiviral therapy: a randomized, controlled study of co-administration of HBsAg/AS02 candidate vaccine and lamivudine. Vaccine 2007; 25 (51) 8585-8597
    CrossrefPubMedGoogle Scholar
  • 79 Sautto GA, Wisskirchen K, Clementi N. , et al. Chimeric antigen receptor (CAR)-engineered T cells redirected against hepatitis C virus (HCV) E2 glycoprotein. Gut 2016; 65 (03) 512-523
    CrossrefPubMedGoogle Scholar
  • 80 Takayama T, Sekine T, Makuuchi M. , et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000; 356 (9232): 802-807
    CrossrefPubMedGoogle Scholar
  • 81 Xu L, Wang J, Kim Y. , et al. A randomized controlled trial on patients with or without adjuvant autologous cytokine-induced killer cells after curative resection for hepatocellular carcinoma. OncoImmunology 2015; 5 (03) e1083671
    PubMedGoogle Scholar
  • 82 Lee JH, Lee JH, Lim YS. , et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 2015; 148 (07) 1383-91.e6
    CrossrefPubMedGoogle Scholar
  • 83 Chew V, Tow C, Huang C. , et al. Toll-like receptor 3 expressing tumor parenchyma and infiltrating natural killer cells in hepatocellular carcinoma patients. J Natl Cancer Inst 2012; 104 (23) 1796-1807
    CrossrefPubMedGoogle Scholar
  • 84 Ohira M, Nishida S, Tryphonopoulos P. , et al. Clinical-scale isolation of interleukin-2-stimulated liver natural killer cells for treatment of liver transplantation with hepatocellular carcinoma. Cell Transplant 2012; 21 (07) 1397-1406
    CrossrefPubMedGoogle Scholar
  • 85 Daher M, Rezvani K. Next generation natural killer cells for cancer immunotherapy: the promise of genetic engineering. Curr Opin Immunol 2018; 51: 146-153
    CrossrefPubMedGoogle Scholar
  • 86 Horst AK, Neumann K, Diehl L, Tiegs G. Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. Cell Mol Immunol 2016; 13 (03) 277-292
    Google Scholar
  • 87 Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 2010; 10 (11) 753-766
    CrossrefPubMedGoogle Scholar
  • 88 Knolle PA, Thimme R. Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology 2014; 146 (05) 1193-1207
    CrossrefPubMedGoogle Scholar
  • 89 Howells A, Marelli G, Lemoine NR, Wang Y. Oncolytic viruses-interaction of virus and tumor cells in the battle to eliminate cancer. Front Oncol 2017; 7: 195
    CrossrefPubMedGoogle Scholar
  • 90 Jhawar SR, Thandoni A, Bommareddy PK. , et al. Oncolytic viruses-natural and genetically engineered cancer immunotherapies. Front Oncol 2017; 7: 202
    CrossrefPubMedGoogle Scholar
  • 91 Yoo SY, Badrinath N, Woo HY, Heo J. Oncolytic virus-based immunotherapies for hepatocellular carcinoma. Mediators Inflamm 2017; 2017: 5198798
    PubMedGoogle Scholar
  • 92 Park BH, Hwang T, Liu TC. , et al. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol 2008; 9 (06) 533-542
    CrossrefPubMedGoogle Scholar
  • 93 Heo J, Reid T, Ruo L. , et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med 2013; 19 (03) 329-336
    CrossrefPubMedGoogle Scholar
  • 94 LaRocca CJ, Warner SG. Oncolytic viruses and checkpoint inhibitors: combination therapy in clinical trials. Clin Transl Med 2018; 7 (01) 35
    PubMedGoogle Scholar
  • 95 Liu TC, Hwang T, Park BH, Bell J, Kirn DH. The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma. Mol Ther 2008; 16 (09) 1637-1642
    CrossrefPubMedGoogle Scholar
  • 96 Buonaguro L, Petrizzo A, Tagliamonte M, Tornesello ML, Buonaguro FM. Challenges in cancer vaccine development for hepatocellular carcinoma. J Hepatol 2013; 59 (04) 897-903
    CrossrefPubMedGoogle Scholar
  • 97 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 (09) 2817-2825
    CrossrefPubMedGoogle Scholar
  • 98 Wang X, Wang Q. Alpha-fetoprotein and hepatocellular carcinoma immunity. Can J Gastroenterol Hepatol 2018; 2018: 9049252
    PubMedGoogle Scholar
  • 99 Tsuchiya N, Yoshikawa T, Fujinami N. , et al. Immunological efficacy of glypican-3 peptide vaccine in patients with advanced hepatocellular carcinoma. OncoImmunology 2017; 6 (10) e1346764
    CrossrefPubMedGoogle Scholar
  • 100 Sawada Y, Yoshikawa T, Ofuji K. , et al. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. OncoImmunology 2016; 5 (05) e1129483
    CrossrefPubMedGoogle Scholar
  • 101 Ott PA, Hu Z, Keskin DB. , et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 2017; 547 (7662): 217-221
    CrossrefPubMedGoogle Scholar
  • 102 Sahin U, Derhovanessian E, Miller M. , et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 2017; 547 (7662): 222-226
    PubMedGoogle Scholar
  • 103 Carreno BM, Magrini V, Becker-Hapak M. , et al. Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 2015; 348 (6236): 803-808
    CrossrefPubMedGoogle Scholar
  • 104 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 (04) 887-896
    CrossrefPubMedGoogle Scholar
  • 105 Kim HD, Song GW, Park S. , et al. Association between expression level of PD1 by tumor-infiltrating CD8+ T cells and features of hepatocellular carcinoma. Gastroenterology 2018; 155 (06) 1936-1950.e17
    CrossrefPubMedGoogle Scholar
  • 106 Boni C, Fisicaro P, Valdatta C. , et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 2007; 81 (08) 4215-4225
    CrossrefPubMedGoogle Scholar
  • 107 Fisicaro P, Valdatta C, Massari M. , et al. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology 2010; 138 (02) 682-693 , 693.e1–693.e4
    CrossrefPubMedGoogle Scholar
  • 108 Yau T, Hsu C, Kim TY. , et al. Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis. J Hepatol 2019; 71 (03) 543-552
    CrossrefPubMedGoogle Scholar
  • 109 Yau T, Kang Y-K, Kim T-Y. , et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. J Clin Oncol 2019; 37: 4012-4012
    CrossrefPubMedGoogle Scholar
  • 110 Finn RS, Ryoo B-Y, Merle P. , et al. Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC). J Clin Oncol 2019; 37: 4004-4004
    CrossrefPubMedGoogle Scholar
  • 111 Thommen DS, Koelzer VH, Herzig P. , et al. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat Med 2018; 24 (07) 994-1004
    CrossrefPubMedGoogle Scholar
  • 112 Flecken T, Schmidt N, Hild S. , et al. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology 2014; 59 (04) 1415-1426
    CrossrefPubMedGoogle Scholar
  • 113 Franceschini D, Paroli M, Francavilla V. , et al. PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. J Clin Invest 2009; 119 (03) 551-564
    CrossrefPubMedGoogle Scholar
  • 114 Kamada T, Togashi Y, Tay C. , et al. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci U S A 2019; 116 (20) 9999-10008
    CrossrefPubMedGoogle Scholar
  • 115 Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res 2017; 27 (01) 109-118
    CrossrefPubMedGoogle Scholar
  • 116 Wainberg ZA, Segal NH, Jaeger D. , et al. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC). J Clin Oncol 2017; 35: 4071-4071
    CrossrefPubMedGoogle Scholar
  • 117 Calderaro J, Rousseau B, Amaddeo G. , et al. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology 2016; 64 (06) 2038-2046
    CrossrefPubMedGoogle Scholar
  • 118 Kelley RK, Abou-Alfa GK, Bendell JC. , et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase I safety and efficacy analyses. J Clin Oncol 2017; 35: 4073-4073
    CrossrefPubMedGoogle Scholar
  • 119 Abou-Alfa GK, Chan SL, Furuse J. , et al. A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study. J Clin Oncol 2018; 36: TPS4144-TPS4144
    CrossrefPubMedGoogle Scholar
  • 120 Abou-Alfa GK, Meyer T, Cheng AL. , et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018; 379 (01) 54-63
    CrossrefPubMedGoogle Scholar
  • 121 Kelley RK, Cheng A-L, Braiteh FS. , et al. Phase 3 (COSMIC-312) study of cabozantinib (C) in combination with atezolizumab (A) versus sorafenib (S) in patients (pts) with advanced hepatocellular carcinoma (aHCC) who have not received previous systemic anticancer therapy. J Clin Oncol 2019; 37: TPS4157-TPS4157
    CrossrefPubMedGoogle Scholar
  • 122 Finn RS, Ducreux M, Qin S. , et al. IMbrave150: a randomized phase III study of 1L atezolizumab plus bevacizumab vs sorafenib in locally advanced or metastatic hepatocellular carcinoma. J Clin Oncol 2018; 36: TPS4141-TPS4141
    CrossrefPubMedGoogle Scholar
  • 123 Li YL, Zhao H, Ren XB. Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward?. Cancer Biol Med 2016; 13 (02) 206-214
    PubMedGoogle Scholar
  • 124 Hansen W, Hutzler M, Abel S. , et al. Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth. J Exp Med 2012; 209 (11) 2001-2016
    CrossrefPubMedGoogle Scholar
  • 125 Hodi FS, O'Day SJ, McDermott DF. , et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363 (08) 711-723
    CrossrefPubMedGoogle Scholar
  • 126 Wolchok JD, Chiarion-Sileni V, Gonzalez R. , et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017; 377 (14) 1345-1356
    CrossrefPubMedGoogle Scholar
  • 127 Sangro B, Gomez-Martin C, de la Mata M. , et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013; 59 (01) 81-88
    CrossrefPubMedGoogle Scholar
  • 128 Stanaway JD, Flaxman AD, Naghavi M. , et al. The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013. Lancet 2016; 388 (10049): 1081-1088
    CrossrefPubMedGoogle Scholar
  • 129 Blonski W, Kotlyar DS, Forde KA. Non-viral causes of hepatocellular carcinoma. World J Gastroenterol 2010; 16 (29) 3603-3615
    CrossrefPubMedGoogle Scholar
  • 130 Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011; 332 (6037): 1519-1523
    CrossrefPubMedGoogle Scholar
  • 131 Karin M. New insights into the pathogenesis and treatment of non-viral hepatocellular carcinoma: a balancing act between immunosuppression and immunosurveillance. Precis Clin Med 2018; 1 (01) 21-28
    CrossrefPubMedGoogle Scholar