Specific CD8+ T cell response immunotherapy for hepatocellular carcinoma and viral hepatitis

World Journal of Gastroenterology

Volumn 22, Issue 28, 2016, Pages 6469-6483

  Moreno Cubero, Elia ^a,b   Larrubia, Juan Ramón ^a,b  

^a HOSPITAL UNIVERSITARIO DE GUADALAJARA   (Spain)

^b UNIVERSITY OF ALCALÁ   (Spain)

Author keywords

CD8+ T cells; Chronic viral hepatitis; Cytotoxic T lymphocyte antigen 4; Hepatocellular carcinoma; Immune checkpoint modulation; Programmed cell death protein 1

Indexed keywords

CD160 PROTEIN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; IPILIMUMAB; LAG 3 PROTEIN; LYMPHOCYTE RECEPTOR; MEMBRANE PROTEIN; NATURAL KILLER CELL RECEPTOR; NATURAL KILLER CELL RECEPTOR 2B4; NIVOLUMAB; NUCLEOSIDE ANALOG; NUCLEOTIDE DERIVATIVE; PEGINTERFERON ALPHA; PEMBROLIZUMAB; PROGRAMMED DEATH 1 LIGAND 1; PROGRAMMED DEATH 1 RECEPTOR; SORAFENIB; T CELL IMMUNOGLOBULIN AND MUCIN DOMAIN CONTAINING 3 PROTEIN; TICILIMUMAB; UNCLASSIFIED DRUG; ANTINEOPLASTIC AGENT; CTLA4 PROTEIN, HUMAN; MONOCLONAL ANTIBODY; PDCD1 PROTEIN, HUMAN;

CD8+ T LYMPHOCYTE; CHRONIC HEPATITIS B; CHRONIC HEPATITIS C; CLINICAL TRIAL (TOPIC); CYTOKINE PRODUCTION; DENDRITIC CELL; HEPATITIS B VIRUS; HEPATITIS C VIRUS; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL TOLERANCE; IMMUNOTHERAPY; KUPFFER CELL; LIVER CELL; LIVER CELL CARCINOMA; LIVER SINUSOID; LIVER SINUSOIDAL ENDOTHELIAL CELL; NONHUMAN; REVIEW; SINGLE DRUG DOSE; STELLATE CELL; T LYMPHOCYTE ACTIVATION; UNSPECIFIED SIDE EFFECT; VIRUS LOAD; ANTAGONISTS AND INHIBITORS; CARCINOMA, HEPATOCELLULAR; IMMUNOLOGY; LIVER NEOPLASMS;

ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC AGENTS; CARCINOMA, HEPATOCELLULAR; CD8-POSITIVE T-LYMPHOCYTES; CTLA-4 ANTIGEN; HEPATITIS C, CHRONIC; HUMANS; LIVER NEOPLASMS; PROGRAMMED CELL DEATH 1 RECEPTOR;

EID: 84979517466     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v22.i28.6469     Document Type: Review

References (136)

1. Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P, Robbins G, Phillips R, Klenerman P, Walker BD. Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 2000; 191: 1499-1512 [PMID: 10790425 DOI: 10.1084/jem.191.9.1499]
2. Cooper S, Erickson AL, Adams EJ, Kansopon J, Weiner AJ, Chien DY, Houghton M, Parham P, Walker CM. Analysis of a successful immune response against hepatitis C virus. Immunity 1999; 10: 439-449 [PMID: 10229187 DOI: 10.1016/S0016-5085(99)70289-1]
3. Smyk-Pearson S, Tester IA, Klarquist J, Palmer BE, Pawlotsky JM, Golden-Mason L, Rosen HR. Spontaneous recovery in acute human hepatitis C virus infection: functional T-cell thresholds and relative importance of CD4 help. J Virol 2008; 82: 1827-1837 [PMID: 18045940 DOI: 10.1128/JVI.01581-07]
4. Larrubia JR, Moreno-Cubero E, Lokhande MU, García-Garzón S, Lázaro A, Miquel J, Perna C, Sanz-de-Villalobos E. Adaptive immune response during hepatitis C virus infection. World J Gastroenterol 2014; 20: 3418-3430 [PMID: 24707125 DOI: 10.3748/wjg.v20.i13.3418]
5. Maini MK, Boni C, Ogg GS, King AS, Reignat S, Lee CK, Larrubia JR, Webster GJ, McMichael AJ, Ferrari C, Williams R, Vergani D, Bertoletti A. Direct ex vivo analysis of hepatitis B virusspecific CD8(+) T cells associated with the control of infection. Gastroenterology 1999; 117: 1386-1396 [PMID: 10579980]
6. Gallimore A, Glithero A, Godkin A, Tissot AC, Plückthun A, Elliott T, Hengartner H, Zinkernagel R. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J Exp Med 1998; 187: 1383-1393 [PMID: 9565631 DOI: 10.1084/jem.187.9.1383]
7. Webster GJ, Reignat S, Maini MK, Whalley SA, Ogg GS, King A, Brown D, Amlot PL, Williams R, Vergani D, Dusheiko GM, Bertoletti A. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology 2000; 32: 1117-1124 [PMID: 11050064 DOI: 10.1053/jhep.2000.19324]
8. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011; 480: 480-489 [PMID: 22193102 DOI: 10.1038/nature10673]
9. Yoong KF, McNab G, Hübscher SG, Adams DH. Vascular adhesion protein-1 and ICAM-1 support the adhesion of tumorinfiltrating lymphocytes to tumor endothelium in human hepatocellular carcinoma. J Immunol 1998; 160: 3978-3988 [PMID: 9558106]
10. Wada Y, Nakashima O, Kutami R, Yamamoto O, Kojiro M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology 1998; 27: 407-414 [PMID: 9462638 DOI: 10.1002/hep.510270214]
11. 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: 802-807 [PMID: 11022927 DOI: 10.1016/S0140-6736(00)02654-4]
12. Flecken T, Schmidt N, Hild S, Gostick E, Drognitz O, Zeiser R, Schemmer P, Bruns H, Eiermann T, Price DA, Blum HE, Neumann-Haefelin C, Thimme R. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology 2014; 59: 1415-1426 [PMID: 24002931 DOI: 10.1002/hep.26731]
13. Bengsch B, Seigel B, Ruhl M, Timm J, Kuntz M, Blum HE, Pircher H, Thimme R. Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog 2010; 6: e1000947 [PMID: 20548953 DOI: 10.1371/journal.ppat.1000947]
14. Wood NA, Linn ML, Bowen DG. Exhausted or just sleeping: awakening virus-specific responses in chronic hepatitis C virus infection. Hepatology 2011; 54: 1879-1882 [PMID: 22038790 DOI: 10.1002/hep.24602]
15. Maini MK, Boni C, Lee CK, Larrubia JR, Reignat S, Ogg GS, King AS, Herberg J, Gilson R, Alisa A, Williams R, Vergani D, Naoumov NV, Ferrari C, Bertoletti A. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 2000; 191: 1269-1280 [PMID: 10770795 DOI: 10.1084/jem.191.8.1269]
16. You CR, Lee SW, Jang JW, Yoon SK. Update on hepatitis B virus infection. World J Gastroenterol 2014; 20: 13293-13305 [PMID: 25309066 DOI: 10.3748/wjg.v20.i37.13293]
17. El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 2008; 134: 1752-1763 [PMID: 18471552 DOI: 10.1053/j.gastro.2008.02.090]
18. Bitton Alaluf M, Shlomai A. New therapies for chronic hepatitis B. Liver Int 2016; 36: 775-782 [PMID: 26854115 DOI: 10.1111/liv.13086]
19. European Association for Study of Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2014; 60: 392-420 [PMID: 24331294 DOI: 10.1016/j.jhep.2013.11.003]
20. Romano E, Romero P. The therapeutic promise of disrupting the PD-1/PD-L1 immune checkpoint in cancer: unleashing the CD8 T cell mediated anti-tumor activity results in significant, unprecedented clinical efficacy in various solid tumors. J Immunother Cancer 2015; 3: 15 [PMID: 25901287 DOI: 10.1186/s40425-015-0059-z]
21. Choudhuri K, Kearney A, Bakker TR, van der Merwe PA. Immunology: how do T cells recognize antigen? Curr Biol 2005; 15: R382-R385 [PMID: 15916940 DOI: 10.1016/j.cub.2005.05.001]
22. Appay V, van Lier RA, Sallusto F, Roederer M. Phenotype and function of human T lymphocyte subsets: consensus and issues. Cytometry A 2008; 73: 975-983 [PMID: 18785267 DOI: 10.1002/cytoa.20643]
23. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 2013; 13: 227-242 [PMID: 23470321 DOI: 10.1038/nri3405]
24. Larrubia JR, Benito-Martínez S, Miquel J, Calvino M, Sanzde-Villalobos E, González-Praetorius A, Albertos S, García-Garzón S, Lokhande M, Parra-Cid T. Bim-mediated apoptosis and PD-1/PD-L1 pathway impair reactivity of PD1(+)/CD127(-) HCVspecific CD8(+) cells targeting the virus in chronic hepatitis C virus infection. Cell Immunol 2011; 269: 104-114 [PMID: 21481848 DOI: 10.1016/j.cellimm.2011.03.011]
25. Peng G, Li S, Wu W, Tan X, Chen Y, Chen Z. PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients. Mol Immunol 2008; 45: 963-970 [PMID: 17868872 DOI: 10.1016/j.molimm.2007.07.038]
26. Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, Zhou J, Li BZ, Shi YH, Xiao YS, Xu Y, Fan J. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 2009; 15: 971-979 [PMID: 19188168 DOI: 10.1158/1078-0432.CCR-08-1608]
27. Nakamoto N, Cho H, Shaked A, Olthoff K, Valiga ME, Kaminski M, Gostick E, Price DA, Freeman GJ, Wherry EJ, Chang KM. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog 2009; 5: e1000313 [PMID: 19247441 DOI: 10.1371/journal. ppat.1000313]
28. Schurich A, Khanna P, Lopes AR, Han KJ, Peppa D, Micco L, Nebbia G, Kennedy PT, Geretti AM, Dusheiko G, Maini MK. Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection. Hepatology 2011; 53: 1494-1503 [PMID: 21360567 DOI: 10.1002/hep.24249]
29. Xu Y, Li H, Gao RL, Adeyemo O, Itkin M, Kaplan DE. Expansion of interferon-gamma-producing multifunctional CD4+ T-cells and dysfunctional CD8+ T-cells by glypican-3 peptide library in hepatocellular carcinoma patients. Clin Immunol 2011; 139: 302-313 [PMID: 21419713 DOI: 10.1016/j.clim.2011.02.014]
30. Sangro B, Gomez-Martin C, de la Mata M, Iñarrairaegui M, Garralda E, Barrera P, Riezu-Boj JI, Larrea E, Alfaro C, Sarobe P, Lasarte JJ, Pérez-Gracia JL, Melero I, Prieto J. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013; 59: 81-88 [PMID: 23466307 DOI: 10.1016/j.jhep.2013.02.022]
31. Gardiner D, Lalezari J, Lawitz E, DiMicco M, Ghalib R, Reddy KR, Chang KM, Sulkowski M, Marro SO, Anderson J, He B, Kansra V, McPhee F, Wind-Rotolo M, Grasela D, Selby M, Korman AJ, Lowy I. A randomized, double-blind, placebocontrolled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection. PLoS One 2013; 8: e63818 [PMID: 23717490 DOI: 10.1371/journal.pone.0063818]
32. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, Ahmed R. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 1998; 188: 2205-2213 [PMID: 9858507 DOI: 10.1084/jem.188.12.2205]
33. Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol 2015; 36: 265-276 [PMID: 25797516 DOI: 10.1016/j.it.2015.02.008]
34. Larrubia JR, Benito-Martínez S, Miquel J, Calvino M, Sanz-de-Villalobos E, Parra-Cid T. Costimulatory molecule programmed death-1 in the cytotoxic response during chronic hepatitis C. World J Gastroenterol 2009; 15: 5129-5140 [PMID: 19891011 DOI: 10.3748/wjg.15.5129]
35. Larrubia JR, Moreno-Cubero E, Miquel J, Sanz-de-Villalobos E. Hepatitis C virus-specific cytotoxic T cell response restoration after treatment-induced hepatitis C virus control. World J Gastroenterol 2015; 21: 3480-3491 [PMID: 25834312 DOI: 10.3748/wjg.v21. i12.3480]
36. Moskophidis D, Lechner F, Pircher H, Zinkernagel RM. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 1993; 362: 758-761 [PMID: 8469287 DOI: 10.1038/362758a0]
37. Larrubia JR, Lokhande MU, García-Garzón S, Miquel J, González-Praetorius A, Parra-Cid T, Sanz-de-Villalobos E. Persistent hepatitis C virus (HCV) infection impairs HCV-specific cytotoxic T cell reactivity through Mcl-1/Bim imbalance due to CD127 down-regulation. J Viral Hepat 2013; 20: 85-94 [PMID: 23301543 DOI: 10.1111/j.1365-2893.2012.01618.x]
38. Bowen DG, Zen M, Holz L, Davis T, McCaughan GW, Bertolino P. The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. J Clin Invest 2004; 114: 701-712 [PMID: 15343389 DOI: 10.1172/JCI21593]
39. Bertolino P, Bowen DG, McCaughan GW, Fazekas de St Groth B. Antigen-specific primary activation of CD8+ T cells within the liver. J Immunol 2001; 166: 5430-5438 [PMID: 11313380 DOI: 10.4049/jimmunol.166.9.5430]
40. Morimoto J, Tan X, Teague RM, Ohlén C, Greenberg PD. Induction of tolerance in CD8+ T cells to a transgenic autoantigen expressed in the liver does not require cross-presentation. J Immunol 2007; 178: 6849-6860 [PMID: 17513733 DOI: 10.4049/jimmunol.178.11.6849]
41. Warren A, Le Couteur DG, Fraser R, Bowen DG, McCaughan GW, Bertolino P. T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatology 2006; 44: 1182-1190 [PMID: 17058232 DOI: 10.1002/hep.21378]
42. Bertolino P. Impaired function of dendritic cells translocating the liver sinusoids: a veto effect contributing to intrahepatic tolerance? Eur J Immunol 2008; 38: 938-941 [PMID: 18395848 DOI: 10.1002/eji.200838296]
43. Holz LE, Benseler V, Bowen DG, Bouillet P, Strasser A, O'Reilly L, d'Avigdor WM, Bishop AG, McCaughan GW, Bertolino P. Intrahepatic murine CD8 T-cell activation associates with a distinct phenotype leading to Bim-dependent death. Gastroenterology 2008; 135: 989-997 [PMID: 18619445 DOI: 10.1053/j.gastro.2008.05.078]
44. Mühlbauer M, Fleck M, Schütz C, Weiss T, Froh M, Blank C, Schölmerich J, Hellerbrand C. PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and-gamma and mediates T cell apoptosis. J Hepatol 2006; 45: 520-528 [PMID: 16876901 DOI: 10.1016/j.jhep.2006.05.007]
45. Maier H, Isogawa M, Freeman GJ, Chisari FV. PD-1: PD-L1 interactions contribute to the functional suppression of virusspecific CD8+ T lymphocytes in the liver. J Immunol 2007; 178: 2714-2720 [PMID: 17312113 DOI: 10.4049/jimmunol.178.5.2714]
46. Mackay IR. Hepatoimmunology: a perspective. Immunol Cell Biol 2002; 80: 36-44 [PMID: 11869361 DOI: 10.1046/j.1440-1711.2002.01063.x]
47. Gale RP, Sparkes RS, Golde DW. Bone marrow origin of hepatic macrophages (Kupffer cells) in humans. Science 1978; 201: 937-938 [PMID: 356266 DOI: 10.1126/science.356266]
48. MacPhee PJ, Schmidt EE, Groom AC. Intermittence of blood flow in liver sinusoids, studied by high-resolution in vivo microscopy. Am J Physiol 1995; 269: G692-G698 [PMID: 7491960]
49. Sun Z, Wada T, Maemura K, Uchikura K, Hoshino S, Diehl AM, Klein AS. Hepatic allograft-derived Kupffer cells regulate T cell response in rats. Liver Transpl 2003; 9: 489-497 [PMID: 12740792 DOI: 10.1053/jlts.2003.50091]
50. Wu K, Kryczek I, Chen L, Zou W, Welling TH. 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 [PMID: 19826049 DOI: 10.1158/0008-5472. CAN-09-0901]
51. Zhang M, Xu S, Han Y, Cao X. Apoptotic cells attenuate fulminant hepatitis by priming Kupffer cells to produce interleukin-10 through membrane-bound TGF-?. Hepatology 2011; 53: 306-316 [PMID: 21140375 DOI: 10.1002/hep.24029]
52. Schurich A, Berg M, Stabenow D, Böttcher J, Kern M, Schild HJ, Kurts C, Schuette V, Burgdorf S, Diehl L, Limmer A, Knolle PA. Dynamic regulation of CD8 T cell tolerance induction by liver sinusoidal endothelial cells. J Immunol 2010; 184: 4107-4114 [PMID: 20212092 DOI: 10.4049/jimmunol.0902580]
53. von Oppen N, Schurich A, Hegenbarth S, Stabenow D, Tolba R, Weiskirchen R, Geerts A, Kolanus W, Knolle P, Diehl L. Systemic antigen cross-presented by liver sinusoidal endothelial cells induces liver-specific CD8 T-cell retention and tolerization. Hepatology 2009; 49: 1664-1672 [PMID: 19205034 DOI: 10.1002/hep.22795]
54. Viñas O, Bataller R, Sancho-Bru P, Ginès P, Berenguer C, Enrich C, Nicolás JM, Ercilla G, Gallart T, Vives J, Arroyo V, Rodés J. Human hepatic stellate cells show features of antigen-presenting cells and stimulate lymphocyte proliferation. Hepatology 2003; 38: 919-929 [PMID: 14512879 DOI: 10.1053/jhep.2003.50392]
55. Li Y, Kim BG, Qian S, Letterio JJ, Fung JJ, Lu L, Lin F. Hepatic Stellate Cells Inhibit T Cells through Active TGF-?1 from a Cell Surface-Bound Latent TGF-?1/GARP Complex. J Immunol 2015; 195: 2648-2656 [PMID: 26246140 DOI: 10.4049/jimmunol.1500139]
56. Lau AH, Thomson AW. Dendritic cells and immune regulation in the liver. Gut 2003; 52: 307-314 [PMID: 12524419 DOI: 10.1136/gut.52.2.307]
57. Khanna A, Morelli AE, Zhong C, Takayama T, Lu L, Thomson AW. Effects of liver-derived dendritic cell progenitors on Th1-and Th2-like cytokine responses in vitro and in vivo. J Immunol 2000; 164: 1346-1354 [PMID: 10640749 DOI: 10.4049/jimmunol.164.3.1346]
58. Buelens C, Verhasselt V, De Groote D, Thielemans K, Goldman M, Willems F. Human dendritic cell responses to lipopolysaccharide and CD40 ligation are differentially regulated by interleukin-10. Eur J Immunol 1997; 27: 1848-1852 [PMID: 9295017 DOI: 10.1002/eji.1830270805]
59. Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M. Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol 2005; 6: 280-286 [PMID: 15685176 DOI: 10.1038/ni1165]
60. El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011; 365: 1118-1127 [PMID: 21992124 DOI: 10.1056/NEJMra1001683]
61. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-674 [PMID: 21376230 DOI: 10.1016/j.cell.2011.02.013]
62. 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: 1448-1457 [PMID: 23174905 DOI: 10.1002/hep.26153]
63. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244: 359-362 [PMID: 2523562]
64. Zhang X. Direct anti-HCV agents. Acta Pharm Sin B 2016; 6: 26-31 [PMID: 26904396 DOI: 10.1016/j.apsb.2015.09.008]
65. Attar BM, Van Thiel DH. Hepatitis C virus: A time for decisions. Who should be treated and when? World J Gastrointest Pharmacol Ther 2016; 7: 33-40 [PMID: 26855810 DOI: 10.4292/wjgpt. v7.i1.33]
66. González-Grande R, Jiménez-Pérez M, González Arjona C, Mostazo Torres J. New approaches in the treatment of hepatitis C. World J Gastroenterol 2016; 22: 1421-1432 [PMID: 26819511 DOI: 10.3748/wjg.v22.i4.1421]
67. Jo J, Aichele U, Kersting N, Klein R, Aichele P, Bisse E, Sewell AK, Blum HE, Bartenschlager R, Lohmann V, Thimme R. Analysis of CD8+ T-cell-mediated inhibition of hepatitis C virus replication using a novel immunological model. Gastroenterology 2009; 136: 1391-1401 [PMID: 19185579 DOI: 10.1053/j.gastro.2008.12.034]
68. Rehermann B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat Med 2013; 19: 859-868 [PMID: 23836236 DOI: 10.1038/nm.3251]
69. Hajarizadeh B, Grebely J, Dore GJ. Epidemiology and natural history of HCV infection. Nat Rev Gastroenterol Hepatol 2013; 10: 553-562 [PMID: 23817321 DOI: 10.1038/nrgastro.2013.107]
70. Chang KM, Rehermann B, McHutchison JG, Pasquinelli C, Southwood S, Sette A, Chisari FV. Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus. J Clin Invest 1997; 100: 2376-2385 [PMID: 9410918 DOI: 10.1172/JCI119778]
71. Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 2006; 1: 23-61 [PMID: 18039107 DOI: 10.1146/annurev.pathol.1.110304.100230]
72. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008; 48: 335-352 [PMID: 18096267 DOI: 10.1016/j.jhep.2007.11.011]
73. European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012; 57: 167-185 [PMID: 22436845 DOI: 10.1016/j.jhep.2012.02.010]
74. Balmasova IP, Yushchuk ND, Mynbaev OA, Alla NR, Malova ES, Shi Z, Gao CL. Immunopathogenesis of chronic hepatitis B. World J Gastroenterol 2014; 20: 14156-14171 [PMID: 25339804 DOI: 10.3748/wjg.v20.i39.14156]
75. Ilan Y, Nagler A, Adler R, Tur-Kaspa R, Slavin S, Shouval D. Ablation of persistent hepatitis B by bone marrow transplantation from a hepatitis B-immune donor. Gastroenterology 1993; 104: 1818-1821 [PMID: 8500741]
76. Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med 1996; 2: 1104-1108 [PMID: 8837608 DOI: 10.1038/nm1096-1104]
77. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711-723 [PMID: 20525992 DOI: 10.1056/NEJMoa1003466]
78. Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P. A new member of the immunoglobulin superfamily-CTLA-4. Nature 1987; 328: 267-270 [PMID: 3496540 DOI: 10.1038/328267a0]
79. Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell 1992; 71: 1065-1068 [PMID: 1335362]
80. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol 1996; 14: 233-258 [PMID: 8717514 DOI: 10.1146/annurev.immunol.14.1.233]
81. Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev 2009; 229: 12-26 [PMID: 19426212 DOI: 10.1111/j.1600-065X.2009.00770.x]
82. Walker LS, Sansom DM. Confusing signals: recent progress in CTLA-4 biology. Trends Immunol 2015; 36: 63-70 [PMID: 25582039 DOI: 10.1016/j.it.2014.12.001]
83. Poggi A, Bottino C, Zocchi MR, Pantaleo G, Ciccone E, Mingari C, Moretta L, Moretta A. CD3+ WT31-peripheral T lymphocytes lack T44 (CD28), a surface molecule involved in activation of T cells bearing the alpha/beta heterodimer. Eur J Immunol 1987; 17: 1065-1068 [PMID: 2440693 DOI: 10.1002/eji.1830170725]
84. Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1994; 1: 793-801 [PMID: 7534620]
85. Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, Brewer JM, Wei B, Hogg N, Garside P, Rudd CE. Reversal of the TCR stop signal by CTLA-4. Science 2006; 313: 1972-1975 [PMID: 16931720 DOI: 10.1126/science.1131078]
86. Xiao Y, Qiao G, Tang J, Tang R, Guo H, Warwar S, Langdon WY, Tao L, Zhang J. Protein Tyrosine Phosphatase SHP-1 Modulates T Cell Responses by Controlling Cbl-b Degradation. J Immunol 2015; 195: 4218-4227 [PMID: 26416283 DOI: 10.4049/jimmunol.1501200]
87. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995; 3: 541-547 [PMID: 7584144]
88. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995; 270: 985-988 [PMID: 7481803]
89. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271: 1734-1736 [PMID: 8596936]
90. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992; 11: 3887-3895 [PMID: 1396582]
91. Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996; 8: 765-772 [PMID: 8671665]
92. Okazaki T, Iwai Y, Honjo T. New regulatory co-receptors: inducible co-stimulator and PD-1. Curr Opin Immunol 2002; 14: 779-782 [PMID: 12413529]
93. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192: 1027-1034 [PMID: 11015443]
94. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001; 2: 261-268 [PMID: 11224527 DOI: 10.1038/85330]
95. Grakoui A, John Wherry E, Hanson HL, Walker C, Ahmed R. Turning on the off switch: regulation of anti-viral T cell responses in the liver by the PD-1/PD-L1 pathway. J Hepatol 2006; 45: 468-472 [PMID: 16901572 DOI: 10.1016/j.jhep.2006.07.009]
96. Rodig N, Ryan T, Allen JA, Pang H, Grabie N, Chernova T, Greenfield EA, Liang SC, Sharpe AH, Lichtman AH, Freeman GJ. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur J Immunol 2003; 33: 3117-3126 [PMID: 14579280 DOI: 10.1002/eji.200324270]
97. Liang SC, Latchman YE, Buhlmann JE, Tomczak MF, Horwitz BH, Freeman GJ, Sharpe AH. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 2003; 33: 2706-2716 [PMID: 14515254 DOI: 10.1002/eji.200324228]
98. Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, Qiu Y, Jussif JM, Carter LL, Wood CR, Chaudhary D. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett 2004; 574: 37-41 [PMID: 15358536 DOI: 10.1016/j.febslet.2004.07.083]
99. Selenko-Gebauer N, Majdic O, Szekeres A, Höfler G, Guthann E, Korthäuer U, Zlabinger G, Steinberger P, Pickl WF, Stockinger H, Knapp W, Stöckl J. B7-H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy. J Immunol 2003; 170: 3637-3644 [PMID: 12646628]
100. Tsushima F, Yao S, Shin T, Flies A, Flies S, Xu H, Tamada K, Pardoll DM, Chen L. Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy. Blood 2007; 110: 180-185 [PMID: 17289811 DOI: 10.1182/blood-2006-11-060087]
101. Goldberg MV, Maris CH, Hipkiss EL, Flies AS, Zhen L, Tuder RM, Grosso JF, Harris TJ, Getnet D, Whartenby KA, Brockstedt DG, Dubensky TW, Chen L, Pardoll DM, Drake CG. Role of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells. Blood 2007; 110: 186-192 [PMID: 17392506 DOI: 10.1182/blood-2006-12-062422]
102. Dong H, Zhu G, Tamada K, Flies DB, van Deursen JM, Chen L. B7-H1 determines accumulation and deletion of intrahepatic CD8(+) T lymphocytes. Immunity 2004; 20: 327-336 [PMID: 15030776]
103. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006; 439: 682-687 [PMID: 16382236 DOI: 10.1038/nature04444]
104. Barathan M, Gopal K, Mohamed R, Ellegård R, Saeidi A, Vadivelu J, Ansari AW, Rothan HA, Ravishankar Ram M, Zandi K, Chang LY, Vignesh R, Che KF, Kamarulzaman A, Velu V, Larsson M, Kamarul T, Shankar EM. Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes. Apoptosis 2015; 20: 466-480 [PMID: 25577277 DOI: 10.1007/s10495-014-1084-y]
105. Penna A, Pilli M, Zerbini A, Orlandini A, Mezzadri S, Sacchelli L, Missale G, Ferrari C. Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection. Hepatology 2007; 45: 588-601 [PMID: 17326153 DOI: 10.1002/hep.21541]
106. Radziewicz H, Ibegbu CC, Fernandez ML, Workowski KA, Obideen K, Wehbi M, Hanson HL, Steinberg JP, Masopust D, Wherry EJ, Altman JD, Rouse BT, Freeman GJ, Ahmed R, Grakoui A. Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J Virol 2007; 81: 2545-2553 [PMID: 17182670 DOI: 10.1128/JVI.02021-06]
107. Fuller MJ, Callendret B, Zhu B, Freeman GJ, Hasselschwert DL, Satterfield W, Sharpe AH, Dustin LB, Rice CM, Grakoui A, Ahmed R, Walker CM. Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1). Proc Natl Acad Sci USA 2013; 110: 15001-15006 [PMID: 23980172 DOI: 10.1073/pnas.1312772110]
108. Fisicaro P, Valdatta C, Massari M, Loggi E, Biasini E, Sacchelli L, Cavallo MC, Silini EM, Andreone P, Missale G, Ferrari C. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology 2010; 138: 682-693, 693.e1-4 [PMID: 19800335 DOI: 10.1053/j.gastro.2009.09.052]
109. Tzeng HT, Tsai HF, Liao HJ, Lin YJ, Chen L, Chen PJ, Hsu PN. PD-1 blockage reverses immune dysfunction and hepatitis B viral persistence in a mouse animal model. PLoS One 2012; 7: e39179 [PMID: 22761734 DOI: 10.1371/journal.pone.0039179]
110. Shi F, Shi M, Zeng Z, Qi RZ, Liu ZW, Zhang JY, Yang YP, Tien P, Wang FS. 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 [PMID: 20473887 DOI: 10.1002/ijc.25397]
111. National Cancer Institute (NCI). Tremelimumab With Chemoembolization or Ablation for Liver Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US), 2013. Available from: URL: https://clinicaltrials.gov/ct2/show/NCT01853618
112. University of Miami. Pembrolizumab (Keytruda) in Advanced Hepatocellular Carcinoma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US), 2016. Available from: URL: https://clinicaltrials.gov/ct2/show/study/NCT02658019#contacts
113. Squibb BM. A Study to Evaluate the Effectiveness, Safety and Tolerability of Nivolumab and the Combination Nivolumab Plus Ipilimumab in Patients With Advanced Liver Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US), 2012 [cited 2016 May 18]. Available from: URL: https://clinicaltrials.gov/ct2/show/NCT01658878
114. Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med 1990; 171: 1393-1405 [PMID: 1692078 DOI: 10.1084/jem.171.5.1393]
115. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DA, Wherry EJ. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 2009; 10: 29-37 [PMID: 19043418 DOI: 10.1038/ni.1679]
116. Chen N, Liu Y, Guo Y, Chen Y, Liu X, Liu M. Lymphocyte activation gene 3 negatively regulates the function of intrahepatic hepatitis C virus-specific CD8+ T cells. J Gastroenterol Hepatol 2015; 30: 1788-1795 [PMID: 26095288 DOI: 10.1111/jgh.13017]
117. Kennedy PT, Sandalova E, Jo J, Gill U, Ushiro-Lumb I, Tan AT, Naik S, Foster GR, Bertoletti A. Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B. Gastroenterology 2012; 143: 637-645 [PMID: 22710188 DOI: 10.1053/j.gastro.2012.06.009]
118. 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: 116-122 [PMID: 23261718 DOI: 10.1016/j.imlet.2012.12.004]
119. Valiante NM, Trinchieri G. Identification of a novel signal transduction surface molecule on human cytotoxic lymphocytes. J Exp Med 1993; 178: 1397-1406 [PMID: 8376943 DOI: 10.1084/jem.178.4.1397]
120. Brown MH, Boles K, van der Merwe PA, Kumar V, Mathew PA, Barclay AN. 2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48. J Exp Med 1998; 188: 2083-2090 [PMID: 9841922]
121. Latchman Y, McKay PF, Reiser H. Identification of the 2B4 molecule as a counter-receptor for CD48. J Immunol 1998; 161: 5809-5812 [PMID: 9834056]
122. Schlaphoff V, Lunemann S, Suneetha PV, Jaroszewicz J, Grabowski J, Dietz J, Helfritz F, Bektas H, Sarrazin C, Manns MP, Cornberg M, Wedemeyer H. Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV-specific CD8+ T cells. PLoS Pathog 2011; 7: e1002045 [PMID: 21625589 DOI: 10.1371/journal.ppat.1002045]
123. Kroy DC, Ciuffreda D, Cooperrider JH, Tomlinson M, Hauck GD, Aneja J, Berger C, Wolski D, Carrington M, Wherry EJ, Chung RT, Tanabe KK, Elias N, Freeman GJ, de Kruyff RH, Misdraji J, Kim AY, Lauer GM. Liver environment and HCV replication affect human T-cell phenotype and expression of inhibitory receptors. Gastroenterology 2014; 146: 550-561 [PMID: 24148617 DOI: 10.1053/j.gastro.2013.10.022]
124. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, Freeman GJ, Kuchroo VK. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002; 415: 536-541 [PMID: 11823861 DOI: 10.1038/415536a]
125. Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 2005; 6: 1245-1252 [PMID: 16286920 DOI: 10.1038/ni1271]
126. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 2010; 207: 2187-2194 [PMID: 20819927 DOI: 10.1084/jem.20100643]
127. Liu Y, Gao LF, Liang XH, Ma CH. Role of Tim-3 in hepatitis B virus infection: An overview. World J Gastroenterol 2016; 22: 2294-2303 [PMID: 26900291 DOI: 10.3748/wjg.v22.i7.2294]
128. McMahan RH, Golden-Mason L, Nishimura MI, McMahon BJ, Kemper M, Allen TM, Gretch DR, Rosen HR. Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. J Clin Invest 2010; 120: 4546-4557 [PMID: 21084749 DOI: 10.1172/JCI43127]
129. Wu W, Shi Y, Li J, Chen F, Chen Z, Zheng M. Tim-3 expression on peripheral T cell subsets correlates with disease progression in hepatitis B infection. Virol J 2011; 8: 113 [PMID: 21392402 DOI: 10.1186/1743-422X-8-113]
130. Wu W, Shi Y, Li S, Zhang Y, Liu Y, Wu Y, Chen Z. Blockade of Tim-3 signaling restores the virus-specific CD8? T-cell response in patients with chronic hepatitis B. Eur J Immunol 2012; 42: 1180-1191 [PMID: 22539292 DOI: 10.1002/eji.201141852]
131. Ngiow SF, von Scheidt B, Akiba H, Yagita H, Teng MW, Smyth MJ. Anti-TIM3 antibody promotes T cell IFN-?-mediated antitumor immunity and suppresses established tumors. Cancer Res 2011; 71: 3540-3551 [PMID: 21430066 DOI: 10.1158/0008-5472. CAN-11-0096]
132. Anumanthan A, Bensussan A, Boumsell L, Christ AD, Blumberg RS, Voss SD, Patel AT, Robertson MJ, Nadler LM, Freeman GJ. Cloning of BY55, a novel Ig superfamily member expressed on NK cells, CTL, and intestinal intraepithelial lymphocytes. J Immunol 1998; 161: 2780-2790 [PMID: 9743336]
133. Kared H, Saeed S, Klein MB, Shoukry NH. CD127 expression, exhaustion status and antigen specific proliferation predict sustained virologic response to IFN in HCV/HIV co-infected individuals. PLoS One 2014; 9: e101441 [PMID: 25007250 DOI: 10.1371/journal.pone.0101441]
134. Viganò S, Banga R, Bellanger F, Pellaton C, Farina A, Comte D, Harari A, Perreau M. CD160-associated CD8 T-cell functional impairment is independent of PD-1 expression. PLoS Pathog 2014; 10: e1004380 [PMID: 25255144 DOI: 10.1371/journal. ppat.1004380]
135. Wu Y, Kuang DM, Pan WD, Wan YL, Lao XM, Wang D, Li XF, Zheng L. Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions. Hepatology 2013; 57: 1107-1116 [PMID: 23225218 DOI: 10.1002/hep.26192]
136. Wenjin Z, Chuanhui P, Yunle W, Lateef SA, Shusen Z. Longitudinal fluctuations in PD1 and PD-L1 expression in association with changes in anti-viral immune response in chronic hepatitis B. BMC Gastroenterol 2012; 12: 109 [PMID: 22894700 DOI: 10.1186/1471-230X-12-109]