Intrahepatic immune changes after hepatitis c virus eradication by direct-acting antiviral therapy.
Adaptor Proteins, Signal Transducing
/ genetics
Aged
Aged, 80 and over
Antiviral Agents
/ therapeutic use
Carcinogenesis
Carcinoma, Hepatocellular
/ genetics
Cytokines
/ genetics
Female
Gene Expression Profiling
Hepacivirus
/ genetics
Hepatitis C, Chronic
/ complications
Humans
Immunohistochemistry
Liver Cirrhosis
/ virology
Liver Neoplasms
/ genetics
Male
Middle Aged
Myxovirus Resistance Proteins
/ genetics
RNA, Viral
/ genetics
RNA-Binding Proteins
/ genetics
Sustained Virologic Response
Tumor Microenvironment
Ubiquitins
/ genetics
direct acting antivirals
hepatitis c virus
hepatocellular carcinoma
immunity
Journal
Liver international : official journal of the International Association for the Study of the Liver
ISSN: 1478-3231
Titre abrégé: Liver Int
Pays: United States
ID NLM: 101160857
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
27
05
2019
revised:
15
08
2019
accepted:
18
08
2019
pubmed:
25
8
2019
medline:
24
3
2021
entrez:
25
8
2019
Statut:
ppublish
Résumé
The recent approval of direct acting anti-virals (DAA) has dramatically changed the landscape of hepatitis C virus (HCV) therapy. Whether viral clearance could promote liver carcinogenesis is debated. It has been hypothesized that changes in intrahepatic immune surveillance following viral cure could favour tumour growth. This study aimed at characterizing the intrahepatic immune changes induced by HCV cure following DAA therapy. Patients with compensated cirrhosis who underwent surgical resection for hepatocellular carcinoma (HCC) after sustained virological response (SVR) to DAA therapy were included. A control group of untreated HCV-infected patients with compensated cirrhosis was selected. RNA was extracted from tumoral and non-tumoral tissues and analysed using the Nanostring Immuno-Oncology-360 panel. Immune cells were quantified by immunohistochemistry. Twenty patients were included: 10 patients with a DAA-induced SVR and 10 untreated controls. All of them had a de novo BCLC 0/A HCC. Non-tumoral tissue profiling showed down-regulation of interferon-related genes (including MX1, ISG15 and IFIT1) after DAA therapy. No other differences in immune profiles/immune cell densities were identified between the two groups. The intra-tumoral immune profiles of HCCs that occurred after DAA therapy were not qualitatively or quantitatively different from those of tumours occurring in untreated patients. In conclusion, removal of HCV infection after DAA-based therapy results only in a down-regulation of interferon-stimulated genes in non-tumoral tissues from patients with cirrhosis who develop HCC. These minor changes in the liver immune microenvironment are unlikely to favour HCC occurrence or recurrence after DAA-induced SVR.
Sections du résumé
BACKGROUND & AIMS
The recent approval of direct acting anti-virals (DAA) has dramatically changed the landscape of hepatitis C virus (HCV) therapy. Whether viral clearance could promote liver carcinogenesis is debated. It has been hypothesized that changes in intrahepatic immune surveillance following viral cure could favour tumour growth. This study aimed at characterizing the intrahepatic immune changes induced by HCV cure following DAA therapy.
METHODS
Patients with compensated cirrhosis who underwent surgical resection for hepatocellular carcinoma (HCC) after sustained virological response (SVR) to DAA therapy were included. A control group of untreated HCV-infected patients with compensated cirrhosis was selected. RNA was extracted from tumoral and non-tumoral tissues and analysed using the Nanostring Immuno-Oncology-360 panel. Immune cells were quantified by immunohistochemistry.
RESULTS
Twenty patients were included: 10 patients with a DAA-induced SVR and 10 untreated controls. All of them had a de novo BCLC 0/A HCC. Non-tumoral tissue profiling showed down-regulation of interferon-related genes (including MX1, ISG15 and IFIT1) after DAA therapy. No other differences in immune profiles/immune cell densities were identified between the two groups. The intra-tumoral immune profiles of HCCs that occurred after DAA therapy were not qualitatively or quantitatively different from those of tumours occurring in untreated patients.
CONCLUSION
In conclusion, removal of HCV infection after DAA-based therapy results only in a down-regulation of interferon-stimulated genes in non-tumoral tissues from patients with cirrhosis who develop HCC. These minor changes in the liver immune microenvironment are unlikely to favour HCC occurrence or recurrence after DAA-induced SVR.
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Antiviral Agents
0
Cytokines
0
IFIT1 protein, human
0
MX1 protein, human
0
Myxovirus Resistance Proteins
0
RNA, Viral
0
RNA-Binding Proteins
0
Ubiquitins
0
ISG15 protein, human
60267-61-0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
74-82Informations de copyright
© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Manns MP, Buti M, Gane ED, et al. Hepatitis C virus infection. Nat Rev Dis Primers. 2017;3:17006. https://doi.org/10.1038/nrdp.2017.6.
Knolle PA, Thimme R. Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology. 2014;146:1193-1207. https://doi.org/10.1053/j.gastro.2013.12.036.
Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005;5:215-229. https://doi.org/10.1038/nri1573.
Horner SM, Gale M Jr. Regulation of hepatic innate immunity by hepatitis C virus. Nat Med. 2013;19:879-888. https://doi.org/10.1038/nm.3253.
Rehermann B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J Clin Investig. 2009;119:1745-1754. https://doi.org/10.1172/JCI39133.
Heim MH, Thimme R. Innate and adaptive immune responses in HCV infections. J Hepatol. 2014;61:S14-25. https://doi.org/10.1016/j.jhep.2014.06.035.
van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308:2584-2593. https://doi.org/10.1001/jama.2012.144878.
Pawlotsky JM. New hepatitis C therapies: the toolbox, strategies, and challenges. Gastroenterology. 2014;146:1176-1192. https://doi.org/10.1053/j.gastro.2014.03.003.
Marshall AD, Pawlotsky J-M, Lazarus JV, Aghemo A, Dore GJ, Grebely J. The removal of DAA restrictions in Europe - One step closer to eliminating HCV as a major public health threat. J Hepatol. 2018;69:1188-1196. https://doi.org/10.1016/j.jhep.2018.06.016.
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;65:719-726. https://doi.org/10.1016/j.jhep.2016.04.008.
Ravi S, Axley P, Jones D et al. Unusually high rates of hepatocellular carcinoma after treatment with direct-acting antiviral therapy for hepatitis c related cirrhosis. Gastroenterology. 2017;152:911-912. https://doi.org/10.1053/j.gastro.2016.12.021.
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;65:727-733. https://doi.org/10.1016/j.jhep.2016.06.015.
Mariño Z, Darnell A, Lens S, et al. Time association between hepatitis C therapy and hepatocellular carcinoma emergence in cirrhosis: relevance of non-characterized nodules. J Hepatol. 2019;70(5):874-884. https://doi.org/10.1016/j.jhep.2019.01.005.
ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT cohorts). Electronic address: stanislas.pol@aphp.fr. Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma. J Hepatol. 2016;65:734-740. https://doi.org/10.1016/j.jhep.2016.05.045.
Nahon P, Layese R, Bourcier V et al. Incidence of hepatocellular carcinoma after direct antiviral therapy for HCV in patients with cirrhosis included in surveillance programs. Gastroenterology. 2018;155(5):1436-1450.e6. https://doi.org/10.1053/j.gastro.2018.07.015.
Nishibatake Kinoshita M, Minami T, Tateishi R, et al. Impact of direct-acting antivirals on early recurrence of HCV-related HCC: Comparison with interferon-based therapy. J Hepatol. 2019;70(1):78-86. https://doi.org/10.1016/j.jhep.2018.09.029.
Minami T, Tateishi R, Nakagomi R, et al. The impact of direct-acting antivirals on early tumor recurrence after radiofrequency ablation in hepatitis C-related hepatocellular carcinoma. J Hepatol. 2016;65:1272-1273. https://doi.org/10.1016/j.jhep.2016.07.043.
Nagata H, Nakagawa M, Asahina Y, et al. Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C. J Hepatol. 2017;67:933-939. https://doi.org/10.1016/j.jhep.2017.05.028.
Virlogeux V, Pradat P, Hartig-Lavie K, et al. Direct-acting antiviral therapy decreases hepatocellular carcinoma recurrence rate in cirrhotic patients with chronic hepatitis C. Liver Int. 2017;37:1122-1127. https://doi.org/10.1111/liv.13456.
Zavaglia C, Okolicsanyi S, Cesarini L, et al. Is the risk of neoplastic recurrence increased after prescribing direct-acting antivirals for HCV patients whose HCC was previously cured? J Hepatol. 2017;66:236-237. https://doi.org/10.1016/j.jhep.2016.08.016.
Cabibbo G, Petta S, Calvaruso V, et al. Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study. Aliment Pharmacol Ther. 2017;46:688-695. https://doi.org/10.1111/apt.14256.
Petta S, Cabibbo G, Barbara M, et al. Hepatocellular carcinoma recurrence in patients with curative resection or ablation: impact of HCV eradication does not depend on the use of interferon. Aliment Pharmacol Ther. 2017;45:160-168. https://doi.org/10.1111/apt.13821.
Calvaruso V, Cabibbo G, Cacciola I, et al. Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting antiviral agents. Gastroenterology. 2018;155(2):411-421.e4. https://doi.org/10.1053/j.gastro.2018.04.008.
Singal AG, Rich NE, Mehta N, et al. Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a multicenter North American cohort study. Gastroenterology. 2019;156(6):1683-1692.e1. https://doi.org/10.1053/j.gastro.2019.01.027.
Romano A, Angeli P, Piovesan S, et al. Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: a prospective population study. J Hepatol. 2018;69:345-352. https://doi.org/10.1016/j.jhep.2018.03.009.
Carrat F, Fontaine H, Dorival C, et al. Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study. Lancet. 2019;393:1453-1464. https://doi.org/10.1016/S0140-6736(18)32111-1.
Piñero F, Mendizabal M, Ridruejo E, et al. Treatment with direct-acting antivirals for HCV decreases but does not eliminate the risk of hepatocellular carcinoma. Liver Int. 2019;39:1033-1043. https://doi.org/10.1111/liv.14041.
Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329-360. https://doi.org/10.1146/annurev.immunol.22.012703.104803.
Fridman WH, Zitvogel L, Sautes-Fridman C, Kroemer G. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol. 2017;14(12):717-734. https://doi.org/10.1038/nrclinonc.2017.101.
Mlecnik B, Bindea G, Pages F, Galon J. Tumor immunosurveillance in human cancers. Cancer Metastasis Rev. 2011;30:5-12. https://doi.org/10.1007/s10555-011-9270-7.
Calderaro J, Couchy G, Imbeaud S, et al. Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J Hepatol. 2017;67(4):727-738. https://doi.org/10.1016/j.jhep.2017.05.014.
Ziol M, Poté N, Amaddeo G, et al. Macrotrabecular-massive hepatocellular carcinoma: a distinctive histological subtype with clinical relevance. Hepatology. 2018;68:103-112. https://doi.org/10.1002/hep.29762.
Calderaro J, Petitprez F, Becht E, et al. Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma. J Hepatol. 2019;70(1):58-65. https://doi.org/10.1016/j.jhep.2018.09.003.
Murakami J, Shimizu Y, Kashii Y, et al. Functional B-cell response in intrahepatic lymphoid follicles in chronic hepatitis C. Hepatology. 1999;30:143-150. https://doi.org/10.1002/hep.510300107.
Finkin S, Yuan D, Stein I, et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat Immunol. 2015;16:1235-1244. https://doi.org/10.1038/ni.3290.
Vandesompele J, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3:RESEARCH0034.
Meissner EG, Kohli A, Higgins J, et al. Rapid changes in peripheral lymphocyte concentrations during interferon-free treatment of chronic hepatitis C virus infection. Hepatol Commun. 2017;1:586-594. https://doi.org/10.1002/hep4.1074.
Putra J, Schiano TD, Fiel MI. Histological assessment of the liver explant in transplanted hepatitis C virus patients achieving sustained virological response with direct-acting antiviral agents. Histopathology. 2018;72:990-996. https://doi.org/10.1111/his.13453.
Perez S, Kaspi A, Domovitz T, et al. Hepatitis C virus leaves an epigenetic signature post cure of infection by direct-acting antivirals. PLoS Genet. 2019;15:e1008181. https://doi.org/10.1371/journal.pgen.1008181.
Hamdane N, Jühling F, Crouchet E, et al. HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response. Gastroenterology. 2019;156(8):2313-2329.e7. https://doi.org/10.1053/j.gastro.2019.02.038
Meissner EG, Wu D, Osinusi A, et al. Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome. J Clin Investig. 2014;124:3352-3363. https://doi.org/10.1172/JCI75938.
Holmes JA, Carlton-Smith C, Kim AY, et al. Dynamic changes in innate immune responses during direct-acting antiviral therapy for HCV infection. J Viral Hepat. 2019;26:362-372. https://doi.org/10.1111/jvh.13041.
Moschos S, Varanasi S, Kirkwood JM. Interferons in the treatment of solid tumors. Cancer Treat Res. 2005;126:207-241.
Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 2006;6:836-848. https://doi.org/10.1038/nri1961.
Tschurtschenthaler M, Wang J, Fricke C, et al. Type I interferon signalling in the intestinal epithelium affects Paneth cells, microbial ecology and epithelial regeneration. Gut. 2014;63:1921-1931. https://doi.org/10.1136/gutjnl-2013-305863.
Guillot B, Portales P, Thanh AD, et al. The expression of cytotoxic mediators is altered in mononuclear cells of patients with melanoma and increased by interferon-alpha treatment. Br J Dermatol. 2005;152:690-696. https://doi.org/10.1111/j.1365-2133.2005.06512.x.
Bacher N, et al. Interferon-alpha suppresses cAMP to disarm human regulatory T cells. Can Res. 2013;73:5647-5656. https://doi.org/10.1158/0008-5472.CAN-12-3788.
Schiavoni G, Mattei F, Gabriele L. Type I interferons as stimulators of DC-mediated cross-priming: impact on anti-tumor response. Front Immunol. 2013;4:483. https://doi.org/10.3389/fimmu.2013.00483.
Spadaro F, et al. IFN-alpha enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing. Blood. 2012;119:1407-1417. https://doi.org/10.1182/blood-2011-06-363564.