Mechanisms and immunotherapies of HBV- and NAFLD-related hepatocellular carcinoma

Xiao-Jia Song , Chun-Hong Ma

Hepatoma Research ›› 2020, Vol. 6 : 27

PDF
Hepatoma Research ›› 2020, Vol. 6:27 DOI: 10.20517/2394-5079.2020.05
Review
Review

Mechanisms and immunotherapies of HBV- and NAFLD-related hepatocellular carcinoma

Author information +
History +
PDF

Abstract

Hepatitis B virus (HBV) infection remains the most important risk factor for hepatocellular carcinoma (HCC) worldwide and nonalcoholic fatty liver disease (NAFLD) has developed as major etiology of chronic liver diseases, cirrhosis and eventually HCC in the last decades. Although nucleos(t)ide analogs are recommended as the first-line drug for patients with chronic hepatitis B, incomplete eradication of HBV serves as an obstacle for effective cure of chronic hepatitis B and even HCC. NAFLD refers to a spectrum of hepatic metabolic disorders, compromised with multi-system diseases. Considering the specificity of hepatocytes and enrichment of immune cells in liver, this review aims to summarize the mechanisms of direct pro-tumorigenesis to hepatocytes induced by HBV infection and abnormal lipid metabolism, and indirect oncogenic processes mediated by immune cells. We also discuss similarities and differences of immune cells between HBV- and NAFLD-HCC and finally focus on the novel immunotherapies concerning preclinical and clinical studies for liver cancer.

Keywords

Hepatitis B virus / nonalcoholic fatty liver disease / hepatocellular carcinoma / immune cells / immunotherapy

Cite this article

Download citation ▾
Xiao-Jia Song, Chun-Hong Ma. Mechanisms and immunotherapies of HBV- and NAFLD-related hepatocellular carcinoma. Hepatoma Research, 2020, 6: 27 DOI:10.20517/2394-5079.2020.05

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Ghany MG,Morgan TR,Aronsohn AI.Hepatitis C guidance 2019 update: AASLD-IDSA recommendations for testing, managing, and treating hepatitis C virus infection..Hepatology2020;71:686-721

[2]

Falade-Nwulia O,Nelson DR,Segal JB.Oral direct-acting agent therapy for hepatitis C virus infection: a systematic review..Ann Intern Med2017;166:637-48 PMCID:PMC5486987

[3]

Cornberg M,Terrault NA.Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference..J Hepatol2019;Epub ahead of print. doi: 10.1002/hep.31030

[4]

Yip TC,Chan HL,Lui GC.Tenofovir is associated with lower risk of hepatocellular carcinoma than entecavir in patients with chronic HBV infection in China..Gastroenterology2020;158:215-25.e6

[5]

Anstee QM,Kotsiliti E,Heikenwalder M.From NASH to HCC: current concepts and future challenges..Nat Rev Gastroenterol Hepatol2019;16:411-28

[6]

Kanwal F,Li L,Natarajan Y.Effect of metabolic traits on the risk of cirrhosis and hepatocellular cancer in non-alcoholic fatty liver disease..Hepatology2020;71:808-19

[7]

Younossi Z,Marietti M,Henry L.Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention..Nat Rev Gastroenterol Hepatol2018;15:11-20

[8]

Younossi Z,Ong JP,Bugianesi E.Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates..Clin Gastroenterol Hepatol2019;17:748-55.e3

[9]

Estes C,Arias-Loste MT,Bellentani S.Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030..J Hepatol2018;69:896-904

[10]

Llovet JM,Pikarsky E,Schwartz M.Hepatocellular carcinoma..Nat Rev Dis Primers2016;2:16018

[11]

Rimassa L,Pressiani T.Management of adverse events associated with tyrosine kinase inhibitors: Improving outcomes for patients with hepatocellular carcinoma..Cancer Treat Rev2019;77:20-8

[12]

Bruix J,Reig M.Insights into the success and failure of systemic therapy for hepatocellular carcinoma..Nat Rev Gastroenterol Hepatol2019;16:617-30

[13]

Brown ZJ,Heinrich B.Adjuvant treatment of hepatocellular carcinoma: prospect of immunotherapy..Hepatology2019;70:1437-42

[14]

Amaddeo G,Ladeiro Y,Nault JC.Integration of tumour and viral genomic characterizations in HBV-related hepatocellular carcinomas..Gut2015;64:820-9 PMCID:PMC4392232

[15]

Hsia CC,Tabor E.Hot-spot mutations in hepatitis B virus X gene in hepatocellular carcinoma..Lancet1996;348:625-6

[16]

Iavarone M,Delpuech O,Colombo M.Characterisation of hepatitis B virus X protein mutants in tumour and non-tumour liver cells using laser capture microdissection..J Hepatol2003;39:253-61

[17]

Ali A,Suhail M,Zakaria MK.Hepatitis B virus, HBx mutants and their role in hepatocellular carcinoma..World J Gastroenterol2014;20:10238-48 PMCID:PMC4130832

[18]

Kim CM,Saito I,Jay G.HBx gene of hepatitis B virus induces liver cancer in transgenic mice..Nature1991;351:317-20

[19]

Kew MC.Hepatitis B virus x protein in the pathogenesis of hepatitis B virus-induced hepatocellular carcinoma..J Gastroenterol Hepatol2011;26:144-52

[20]

Jiang T,Wu J.Structural and biochemical analysis of Bcl-2 interaction with the hepatitis B virus protein HBx..Proc Natl Acad Sci U S A2016;113:2074-9 PMCID:PMC4776483

[21]

Niu Y,Slagle BL,Li S.Farnesoid X receptor ablation sensitizes mice to hepatitis b virus X protein-induced hepatocarcinogenesis..Hepatology2017;65:893-906 PMCID:PMC5319891

[22]

Jegal ME,Han YS.C-terminal truncated HBx reduces doxorubicin cytotoxicity via ABCB1 upregulation in Huh-7 hepatocellular carcinoma cells..BMB Rep2019;52:330-5 PMCID:PMC6549916

[23]

Li Y,Hu X,Tang D.The HBx-CTTN interaction promotes cell proliferation and migration of hepatocellular carcinoma via CREB1..Cell Death Dis2019;10:405 PMCID:PMC6538608

[24]

Lee S,Ko C.Hepatitis B virus X protein enhances Myc stability by inhibiting SCF(Skp2) ubiquitin E3 ligase-mediated Myc ubiquitination and contributes to oncogenesis..Oncogene2016;35:1857-67

[25]

Wang J,Huang ZB,Yu SM.HBx regulates transcription factor PAX8 stabilization to promote the progression of hepatocellular carcinoma..Oncogene2019;38:6696-710

[26]

He B,Li W.Interaction of lncRNA-MALAT1 and miR-124 regulates HBx-induced cancer stem cell properties in HepG2 through PI3K/Akt signaling..J Cell Biochem2019;120:2908-18

[27]

Lin X,Luo R,Yu G.HBX-induced miR-5188 impairs FOXO1 to stimulate beta-catenin nuclear translocation and promotes tumor stemness in hepatocellular carcinoma..Theranostics2019;9:7583-98 PMCID:PMC6831466

[28]

Chen SL,Liu LL,Pan YH.A GYS2/p53 negative feedback loop restricts tumor growth in HBV-related hepatocellular carcinoma..Cancer Res2019;79:534-45

[29]

Liu WC,Lee YC,Cheng JH.Hepatocellular carcinoma-associated single-nucleotide variants and deletions identified by the use of genome-wide high-throughput analysis of hepatitis B virus..J Pathol2017;243:176-92

[30]

Bai X,Fang M,Liang X.Deep sequencing of HBV pre-S region reveals high heterogeneity of HBV genotypes and associations of word pattern frequencies with HCC..PLoS Genet2018;14:e1007206 PMCID:PMC5841821

[31]

Huang JT,Wang J,Yang Y.Next generation digital PCR measurement of hepatitis B virus copy number in formalin-fixed paraffin-embedded hepatocellular carcinoma tissue..Clin Chem2015;61:290-6

[32]

Hsieh YH,Wang HC,Lei HY.Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage..Carcinogenesis2004;25:2023-32

[33]

Pollicino T,Saffioti F.Hepatitis B virus PreS/S gene variants: pathobiology and clinical implications..J Hepatol2014;61:408-17

[34]

Li TN,Tsai HW,Wu YH.Intrahepatic hepatitis B virus large surface antigen induces hepatocyte hyperploidy via failure of cytokinesis..J Pathol2018;245:502-13

[35]

Liu P,Liang X,Luan F.HBV preS2 promotes the expression of TAZ via miRNA-338-3p to enhance the tumorigenesis of hepatocellular carcinoma..Oncotarget2015;6:29048-59 PMCID:PMC4745710

[36]

Luan F,Zhang J,Zhang B.Correlation between HBV protein preS2 and tumor markers of hepatocellular carcinoma..Pathol Res Pract2017;213:1037-42

[37]

Zhang R,Liu C,Gerken G.Hepatic expression of oncogenes Bmi1 and Dkk1 is up-regulated in hepatitis B virus surface antigen-transgenic mice and can be induced by treatment with HBV particles or lipopolysaccharides in vitro..Int J Cancer2017;141:354-63

[38]

Luan F,Gao L,Sun Z.Hepatitis B virus protein preS2 potentially promotes HCC development via its transcriptional activation of hTERT..Gut2009;58:1528-37

[39]

Tseng TC,Hsu CY,Su TH.High level of hepatitis B core-related antigen associated with increased risk of hepatocellular carcinoma in patients with chronic HBV infection of intermediate viral load..Gastroenterology2019;157:1518-29.e3

[40]

Liu W,Jing ZT,Liu L.Hepatitis B virus core protein promotes hepatocarcinogenesis by enhancing Src expression and activating the Src/PI3K/Akt pathway..FASEB J2018;32:3033-46

[41]

Liu D,Wang Y,He J.Hepatitis B e antigen and its precursors promote the progress of hepatocellular carcinoma by interacting with NUMB and decreasing p53 activity..Hepatology2016;64:390-404

[42]

Xie Q,Wei W,Xu Z.Multi-omics analyses reveal metabolic alterations regulated by hepatitis B virus core protein in hepatocellular carcinoma cells..Sci Rep2017;7:41089 PMCID:PMC5253728

[43]

Du J,Liu Y,Gao L.Hepatitis B virus core protein inhibits TRAIL-induced apoptosis of hepatocytes by blocking DR5 expression..Cell Death Differ2009;16:219-29

[44]

Liu W,Yan XL,Wu YL.Hepatitis B virus core protein inhibits Fas-mediated apoptosis of hepatoma cells via regulation of mFas/FasL and sFas expression..FASEB J2015;29:1113-23

[45]

Tu T,Vondran FWR,Urban S.Hepatitis B virus DNA integration occurs early in the viral life cycle in an in vitro infection model via sodium taurocholate cotransporting polypeptide-dependent uptake of enveloped virus particles..J Virol2018;92: PMCID:PMC5952132

[46]

Duan M,Cui S,Zhang S.Diverse modes of clonal evolution in HBV-related hepatocellular carcinoma revealed by single-cell genome sequencing..Cell Res2018;28:359-73 PMCID:PMC5835770

[47]

Zhao LH,Yan HX,Zeng X.Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma..Nat Commun2016;7:12992 PMCID:PMC5059470

[48]

Yang X,Lin J,Wan X.Distinct hepatitis B virus integration patterns in hepatocellular carcinoma and adjacent normal liver tissue..Int J Cancer2017;140:1324-30

[49]

Wong DK,Mak LL,Lo RC.Among patients with undetectable hepatitis B surface antigen and hepatocellular carcinoma, a high proportion has integration of HBV DNA into hepatocyte DNA and no cirrhosis..Clin Gastroenterol Hepatol2020;18:449-56

[50]

Yan H,Zhang L,Wang Y.Characterization of the genotype and integration patterns of hepatitis B virus in early- and late-onset hepatocellular carcinoma..Hepatology2015;61:1821-31

[51]

Chiu YT,Choi SW,Ho DW.Novel pre-mRNA splicing of intronically integrated HBV generates oncogenic chimera in hepatocellular carcinoma..J Hepatol2016;64:1256-64

[52]

Li CL,Lin YY,Chen DS.Androgen receptor enhances hepatic telomerase reverse transcriptase gene transcription after hepatitis B virus integration or point mutation in promoter region..Hepatology2019;69:498-512

[53]

Yoo S,Wang Q,Lee E.A pilot systematic genomic comparison of recurrence risks of hepatitis B virus-associated hepatocellular carcinoma with low- and high-degree liver fibrosis..BMC Med2017;15:214 PMCID:PMC5719570

[54]

Hama N,Miura F,Saito-Adachi M.Epigenetic landscape influences the liver cancer genome architecture..Nat Commun2018;9:1643 PMCID:PMC5915380

[55]

Ren L,Tang Z,Wang X.The antiresection activity of the X protein encoded by hepatitis virus B..Hepatology2019;69:2546-61 PMCID:PMC6618260

[56]

Musa J,Grunewald TG.Hepatitis B virus large surface protein is priming for hepatocellular carcinoma development via induction of cytokinesis failure..J Pathol2019;247:6-8

[57]

Hsieh YH,Su IJ,Liu YR.Hepatitis B virus pre-S2 mutant large surface protein inhibits DNA double-strand break repair and leads to genome instability in hepatocarcinogenesis..J Pathol2015;236:337-47

[58]

Takakura K,Nakano M,Torisu Y.Recent insights into the multiple pathways driving non-alcoholic steatohepatitis-derived hepatocellular carcinoma..Front Oncol2019;9:762 PMCID:PMC6700399

[59]

Li T,Zhang Y,Fu G.mTOR direct crosstalk with STAT5 promotes de novo lipid synthesis and induces hepatocellular carcinoma..Cell Death Dis2019;10:619 PMCID:PMC6692326

[60]

Tian Y,Qiu W,Zhang Z.ER-residential Nogo-B accelerates NAFLD-associated HCC mediated by metabolic reprogramming of oxLDL lipophagy..Nat Commun2019;10:3391 PMCID:PMC6662851

[61]

Kodama T,Newberg JY,Wu H.Molecular profiling of nonalcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis..Proc Natl Acad Sci U S A2018;115:e10417-26 PMCID:PMC6217425

[62]

Ye J,Xu G,Zhang NP.JCAD promotes progression of nonalcoholic steatohepatitis to liver cancer by inhibiting LATS2 kinase activity..Cancer Res2017;77:5287-300

[63]

Jeong SH,Kim MC,Lee JH.Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer..J Clin Invest2018;128:1010-25 PMCID:PMC5824861

[64]

Inoue-Yamauchi A,Oda H.Eicosapentaenoic acid attenuates obesity-related hepatocellular carcinogenesis..Carcinogenesis2018;39:28-35 PMCID:PMC5862334

[65]

Kumar DP,Seneshaw M,Uram-Tuculescu C.A regulatory role of apoptosis antagonizing transcription factor in the pathogenesis of nonalcoholic fatty liver disease and hepatocellular carcinoma..Hepatology2019;69:1520-34 PMCID:PMC6440548

[66]

He Y,Cai Y,Xu M.MicroRNA-223 ameliorates nonalcoholic steatohepatitis and cancer by targeting multiple inflammatory and oncogenic genes in hepatocytes..Hepatology2019;70:1150-67 PMCID:PMC6783322

[67]

Namjou B,Huang Y,Cobb BL.GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network..BMC Med2019;17:135 PMCID:PMC6636057

[68]

Grimaudo S,Pennisi G,Camma C.Association between PNPLA3 rs738409 C>G variant and liver-related outcomes in patients with non-alcoholic fatty liver disease..Clin Gastroenterol Hepatol2020;18:935-44.e3

[69]

Tepper CG,Stewart SL,Wong KA.High frequency of the PNPLA3 rs738409 [G] single-nucleotide polymorphism in Hmong individuals as a potential basis for a predisposition to chronic liver disease..Cancer2018;124:1583-9 PMCID:PMC5875707

[70]

Petta S,Tuttolomondo A,Pipitone RM.Interferon lambda 4 rs368234815 TT>deltaG variant is associated with liver damage in patients with nonalcoholic fatty liver disease..Hepatology2017;66:1885-93

[71]

Petta S,Svegliati-Baroni G,Pipitone RM.Fibronectin type III domain-containing protein 5 rs3480 A>G polymorphism, irisin, and liver fibrosis in patients with nonalcoholic fatty liver disease..J Clin Endocrinol Metab2017;102:2660-9

[72]

Cheng YW,Kuo HC,Lin WH.Specific diacylglycerols generated by hepatic lipogenesis stimulate the oncogenic androgen receptor activity in male hepatocytes..Int J Obes (Lond)2019;43:2469-79

[73]

Campisano S,Echarte SM.Interplay between early-life malnutrition, epigenetic modulation of the immune function and liver diseases..Nutr Res Rev2019;32:128-45

[74]

Fridman WH,Sautes-Fridman C.The immune contexture in human tumours: impact on clinical outcome..Nat Rev Cancer2012;12:298-306

[75]

Yan W,Ma H,Song X.Tim-3 fosters HCC development by enhancing TGF-beta-mediated alternative activation of macrophages..Gut2015;64:1593-604

[76]

Faure-Dupuy S,Aillot L,Lebosse F.Hepatitis B virus-induced modulation of liver macrophage function promotes hepatocyte infection..J Hepatol2019;71:1086-98

[77]

Bility MT,Zhang Z,Li F.Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human-specific liver fibrosis and M2-like macrophages..PLoS Pathog2014;10:e1004032 PMCID:PMC3961374

[78]

Cheng X,Serti E,Chung M.Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages..Hepatology2017;66:1779-93 PMCID:PMC5706781

[79]

Tian Y,Akbari O.Maternal-derived hepatitis B virus e antigen alters macrophage function in offspring to drive viral persistence after vertical transmission..Immunity2016;44:1204-14 PMCID:PMC4871724

[80]

Chen J,Chen Y,Zhang Y.Matrix metalloproteinase 9 facilitates hepatitis B virus replication through binding with type i interferon (IFN) receptor 1 to repress IFN/JAK/STAT signaling..J Virol2017;91: PMCID:PMC5375666

[81]

Zang M,He H,Chen K.IL-23 production of liver inflammatory macrophages to damaged hepatocytes promotes hepatocellular carcinoma development after chronic hepatitis B virus infection..Biochim Biophys Acta Mol Basis Dis2018;1864:3759-70

[82]

de Oliveira S,Graves AL,Korte BG.Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish..J Hepatol2019;70:710-21 PMCID:PMC6436385

[83]

Malehmir M,Gallage S,Inverso D.Platelet GPIbalpha is a mediator and potential interventional target for NASH and subsequent liver cancer..Nat Med2019;25:641-55

[84]

Eckert C,Kornek M.The complex myeloid network of the liver with diverse functional capacity at steady state and in inflammation..Front Immunol2015;6:179 PMCID:PMC4403526

[85]

Walenbergh SM,Hendrikx T,van Gorp PJ.Weekly treatment of 2-hydroxypropyl-beta-cyclodextrin improves intracellular cholesterol levels in LDL receptor knockout mice..Int J Mol Sci2015;16:21056-69 PMCID:PMC4613241

[86]

Leroux A,Godie V,Renoud ML.Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis..J Hepatol2012;57:141-9

[87]

Alisi A,Oliveira FL,Nobili V.The role of tissue macrophage-mediated inflammation on NAFLD pathogenesis and its clinical implications..Mediators Inflamm2017;2017:8162421 PMCID:PMC5237469

[88]

Liu XL,Cao HX,Zhao ZH.Lipotoxic hepatocyte-derived exosomal mir-192-5p activates macrophages via Rictor/Akt/FoxO1 signaling in NAFLD..Hepatology2019;Epub ahead of print. doi: 10.1002/hep.31050

[89]

Luo X,Ma L,Guo X.Expression of STING is increased in liver tissues from patients with NAFLD and promotes macrophage-mediated hepatic inflammation and fibrosis in mice..Gastroenterology2018;155:1971-84.e4 PMCID:PMC6279491

[90]

Yang F,Zhou C,Zhu M.Hepatitis B e antigen induces the expansion of monocytic myeloid-derived suppressor cells to dampen T-cell function in chronic hepatitis B virus infection..PLoS Pathog2019;15:e1007690 PMCID:PMC6472891

[91]

Fang Z,Yu X,Ren G.Polarization of monocytic myeloid-derived suppressor cells by hepatitis b surface antigen is mediated via ERK/IL-6/STAT3 signaling feedback and restrains the activation of T cells in chronic hepatitis B virus infection..J Immunol2015;195:4873-83

[92]

Yu Z,Feng H,Li MS.Cell cycle-related kinase mediates viral-host signalling to promote hepatitis B virus-associated hepatocarcinogenesis..Gut2014;63:1793-804

[93]

Zhou J,Sun H,Xu L.Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy..Gut2018;67:931-44 PMCID:PMC5961939

[94]

Sun H,Tian Y,Zhou J.An inflammatory-CCRK circuitry drives mTORC1-dependent metabolic and immunosuppressive reprogramming in obesity-associated hepatocellular carcinoma..Nat Commun2018;9:5214 PMCID:PMC6283830

[95]

Tsunashima H,Moritoki Y,Kikuchi K.Accumulated myeloid-derived suppressor cells demonstrate distinct phenotypes and functions in two non-alcoholic steatohepatitis mouse models..Hepatobiliary Surg Nutr2015;4:313-9 PMCID:PMC4607837

[96]

Yao L,Kawasaki K,Matsuura B.Characterization of liver monocytic myeloid-derived suppressor cells and their role in a murine model of non-alcoholic fatty liver disease..PLoS One2016;11:e0149948 PMCID:PMC4762771

[97]

Pallmer K.Recognition and regulation of T cells by NK cells..Front Immunol2016;7:251 PMCID:PMC4919350

[98]

Biron CA.Is there natural killer cell memory and can it be harnessed by vaccination? Can natural killer and CD8 T cells switch jobs?.Cold Spring Harb Perspect Biol2018;10:

[99]

Harmon C,Fahey R,Houlihan DD.Tissue-resident Eomes(hi) T-bet(lo) CD56(bright) NK cells with reduced proinflammatory potential are enriched in the adult human liver..Eur J Immunol2016;46:2111-20

[100]

Stegmann KA,Hansi N,Pallant C.CXCR6 marks a novel subset of T-bet(lo)Eomes(hi) natural killer cells residing in human liver..Sci Rep2016;6:26157 PMCID:PMC4876507

[101]

Ju Y,Meng J,Zhang X.T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B..J Hepatol2010;52:322-9

[102]

Li H,Wang Z,Yang Y.Regulatory NK cells mediated between immunosuppressive monocytes and dysfunctional T cells in chronic HBV infection..Gut2018;67:2035-44 PMCID:PMC6176520

[103]

Yang Y,Hou Z,Tian Z.Exosomes mediate hepatitis B virus (HBV) transmission and NK-cell dysfunction..Cell Mol Immunol2017;14:465-75 PMCID:PMC5423088

[104]

Shi J,Zhang X,Hu J.Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-beta-dependent emperipolesis in HBV cirrhotic patients..Sci Rep2017;7:44544 PMCID:PMC5349579

[105]

Zhong R,Fu M,Liu L.LINC01149 variant modulates MICA expression that facilitates hepatitis B virus spontaneous recovery but increases hepatocellular carcinoma risk..Oncogene2020;39:1944-56

[106]

Cepero-Donates Y,Ghobadi F,Orkhis S.Interleukin-15-mediated inflammation promotes non-alcoholic fatty liver disease..Cytokine2016;82:102-11

[107]

Cuff AO,Dertschnig S,Luong TV.The obese liver environment mediates conversion of NK cells to a less cytotoxic ILC1-like phenotype..Front Immunol2019;10:2180 PMCID:PMC6749082

[108]

Amer J,Noureddin M,Abu-Tair L.Insulin signaling as a potential natural killer cell checkpoint in fatty liver disease..Hepatol Commun2018;2:285-98 PMCID:PMC5831020

[109]

Tosello-Trampont AC,Narayanan S,Leitinger N.NKp46(+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice..Hepatology2016;63:799-812 PMCID:PMC4764418

[110]

Li Y,Guo L,Gu S.CXCL13-mediated recruitment of intrahepatic CXCR5(+)CD8(+) T cells favors viral control in chronic HBV infection..J Hepatol2020;72:420-30

[111]

Salimzadeh L,Dutertre CA,Newell EW.PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection..J Clin Invest2018;128:4573-87 PMCID:PMC6159957

[112]

Burton AR,McCoy LE,Amin OE.Circulating and intrahepatic antiviral B cells are defective in hepatitis B..J Clin Invest2018;128:4588-603 PMCID:PMC6159997

[113]

Kim HD,Park S,Kim MH.Association between expression level of PD1 by tumor-infiltrating CD8(+) T cells and features of hepatocellular carcinoma..Gastroenterology2018;155:1936-50.e17

[114]

Wang X,Shen H,Tian W.TOX promotes the exhaustion of antitumor CD8(+) T cells by preventing PD1 degradation in hepatocellular carcinoma..J Hepatol2019;71:731-41

[115]

Zheng C,Yoo JK,Zhang Y.Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing..Cell2017;169:1342-56.e16

[116]

Kim GA,Han S,Shim JH.High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B..Gut.2018;67:945-52

[117]

Ghazarian M,Nohr MK,Zeng K.Type I interferon responses drive intrahepatic T cells to promote metabolic syndrome..Sci Immunol2017;2:pii: eaai7616 PMCID:PMC5447456

[118]

Shalapour S,Bastian IN,Burt AD.Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity..Nature2017;551:340-5 PMCID:PMC5884449

[119]

Meng F,Song B.HBV-specific CD4+ cytotoxic T cells in hepatocellular carcinoma are less cytolytic toward tumor cells and suppress CD8+ T cell-mediated antitumor immunity..APMIS2017;125:743-51

[120]

Wang X,Li Q,Zhao D.Dysregulated response of follicular helper T cells to hepatitis B surface antigen promotes HBV persistence in mice and associates with outcomes of patients..Gastroenterology2018;154:2222-36

[121]

Publicover J,Jespersen JM,Johnson AJ.An OX40/OX40L interaction directs successful immunity to hepatitis B virus..Sci Transl Med2018;10: PMCID:PMC6018058

[122]

Jacobi FJ,Smits M,Csernalabics B.OX40 stimulation and PD-L1 blockade synergistically augment HBV-specific CD4 T cells in patients with HBeAg-negative infection..J Hepatol2019;70:1103-13

[123]

Walker CM.Getting the skinny on CD4(+) T cell survival in fatty livers..Immunity2016;44:725-7 PMCID:PMC5381269

[124]

Brown ZJ,Ma C,Zhang H.Carnitine palmitoyltransferase gene upregulation by linoleic acid induces CD4(+) T cell apoptosis promoting HCC development..Cell Death Dis2018;9:620 PMCID:PMC5966464

[125]

Ma C,Eggert T,Kleiner DE.NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis..Nature2016;531:253-7 PMCID:PMC4786464

[126]

Vanwolleghem T,van Oord G,Osterhaus AD.Re-evaluation of hepatitis B virus clinical phases by systems biology identifies unappreciated roles for the innate immune response and B cells..Hepatology2015;62:87-100

[127]

Bertoletti A.Adaptive immunity in HBV infection..J Hepatol2016;64:S71-83

[128]

Zhang S,Zhang Z.Humoral immunity, the underestimated player in hepatitis B..Cell Mol Immunol2018;15:645-8 PMCID:PMC6078975

[129]

Poonia B,Nandi M,Kottilil S.HBV induces inhibitory FcRL receptor on B cells and dysregulates B cell-T follicular helper cell axis..Sci Rep2018;8:15296 PMCID:PMC6193006

[130]

Tout I,Ainouze M,Pecoul T.Hepatitis B virus Blocks the CRE/CREB Complex and Prevents TLR9 Transcription and Function in Human B Cells..J Immunol2018;201:2331-44

[131]

Schwenger KJP,Chelliah A,Teterina A.Markers of activated inflammatory cells are associated with disease severity and intestinal microbiota in adults with nonalcoholic fatty liver disease..Int J Mol Med2018;42:2229-37

[132]

Zhang F,Li X,Wu Z.Role of intrahepatic B cells in non-alcoholic fatty liver disease by secreting pro-inflammatory cytokines and regulating intrahepatic T cells..J Dig Dis2016;17:464-74

[133]

Bruzzi S,Giudici G,Ramavath NN.B2-Lymphocyte responses to oxidative stress-derived antigens contribute to the evolution of nonalcoholic fatty liver disease (NAFLD)..Free Radic Biol Med2018;124:249-59

[134]

Zhang JC,Alvarez JB,Shi L.Cancer immune checkpoint blockade therapy and its associated autoimmune cardiotoxicity..Acta Pharmacol Sin2018;39:1693-8 PMCID:PMC6289335

[135]

El-Khoueiry AB,Yau T,Kudo M.Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial..Lancet2017;389:2492-502

[136]

Yau T,Kim TY,Kang YK.Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis..J Hepatol2019;71:543-52

[137]

Finn RS,Merle P,Bouattour M.Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial..J Clin Oncol2020;38:193-202

[138]

Pishvaian MJ,Ryoo BY,Lee KH.Updated safety and clinical activity results from a phase Ib study of atezolizumab + bevacizumab in hepatocellular carcinoma (HCC)..Ann Oncol2018;29:viii718-9

[139]

Roche’s Tecentriq in combination with Avastin increased overall survival and progression-free survival in people with unresectable hepatocellular carcinoma. Available from: https://www.roche.com/media/releases/med-cor-2019-10-21.htm [Last accessed on 14 Apr 2020]

[140]

Faivre S,Finn RS.Molecular therapies for HCC: looking outside the box..J Hepatol2020;72:342-52

[141]

Tang ZS,Zhang EJ,Zhou Y.CD28 family of receptors on T cells in chronic HBV infection: Expression characteristics, clinical significance and correlations with PD-1 blockade..Mol Med Rep2016;14:1107-16 PMCID:PMC4940091

[142]

Yin Y,Song J,Zhang E.DNA immunization with fusion of CTLA-4 to hepatitis B virus (HBV) core protein enhanced Th2 type responses and cleared HBV with an accelerated kinetic..PLoS One2011;6:e22524 PMCID:PMC3142188

[143]

Schurich A,Lopes AR,Peppa D.Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection..Hepatology2011;53:1494-503

[144]

Wang X,Shen H,Sun B.Genetic and phenotypic difference in CD8(+) T cell exhaustion between chronic hepatitis B infection and hepatocellular carcinoma..J Med Genet2019;56:18-21 PMCID:PMC6327916

[145]

Sangro B,de la Mata M,Garralda E.A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C..J Hepatol2013;59:81-8

[146]

Duffy AG,Makorova-Rusher O,Wedemeyer H.Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma..J Hepatol2017;66:545-51 PMCID:PMC5316490

[147]

Kelley RK,Bendel JC,Borad MJ.Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase I safety and efficacy analyses..J Clin Oncol2017;35:

[148]

Grupp SA,Barrett D,Porter DL.Chimeric antigen receptor-modified T cells for acute lymphoid leukemia..New Engl J Med2013;368:1509-18

[149]

Maude SL,Shaw PA,Barrett DM.Chimeric antigen receptor T cells for sustained remissions in leukemia..New Engl J Med2014;371:1507-17 PMCID:PMC4267531

[150]

Brudno JN,Hartman SD,Wang M.T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma..J Clin Oncol2018;36:2267 PMCID:PMC6067798

[151]

Gao H,Tu H,Jiang H.Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma..Clin Cancer Res2014;20:6418-28

[152]

Wu X,Shi B,Sun R.Combined antitumor effects of sorafenib and GPC3-CAR T cells in mouse models of hepatocellular carcinoma..Mol Ther2019;27:1483-94 PMCID:PMC6697347

[153]

Maude SL,Teachey DT.Managing cytokine release syndrome associated with novel T cell-engaging therapies..Cancer J2014;20:119-22 PMCID:PMC4119809

[154]

Oelsner S,Billmeier A,Lindner A.Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth..Int J Cancer2019;145:1935-45

[155]

Chu J,Benson DM,Hughes T.CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma..Leukemia2014;28:917-27 PMCID:PMC3967004

[156]

Xiao L,Gan H,Huang N.Adoptive transfer of NKG2D CAR mRNA-engineered natural killer cells in colorectal cancer patients..Mol Ther2019;27:1114-25 PMCID:PMC6554529

[157]

Zhang C,Jennewein L,Schonfeld K.ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma..J Natl Cancer Inst2016;108:

PDF

62

Accesses

0

Citation

Detail

Sections
Recommended

/