[1] FORNER A,REIG M,BRUIX J.Hepatocellular carcinoma[J].Lancet,2018,391(10127):1301-1314.
[2] MARQUARDT JU,ANDERSEN,THORGEIRSSON SS.Functional and genetic deconstruction of the cellular origin in liver cancer[J].Nat Rev Cancer,2015,15(11):653-667.
[3] SCHULZE K,NAULT JC,VILLANUEVA A.Genetic profiling of hepatocellular carcinoma using next-generation sequencing[J].J Hepatol,2016,65(5):1031-1042.
[4] OSAKI Y,NISHIKAWA H.Treatment for hepatocellular carcinoma in Japan over the last three decades:Our experience and published work review[J].Hepatol Res,2015,45(1):59-74.
[5] SAKAGUCHI S,SAKAGUCHI N,ASANO M,et al.Immunologic self-Tolerance maintained by activated T cells expressing IL-2 receptor alpha-Chains(CD25) breakdown of a single mechanism of self-tolerance causes various autoimmune diseases[J].J Immunol,2011,186(7):1151-1164.
[6] HORI S,NOMURA T,SAKAGUCHI S.Control of regulatory T cell development by the transcription factor Foxp3[J].Science,2003,299(5609):1057-1061.
[7] TANAKA A,SAKAGUCHI S.Regulatory T cells in cancer immunotherapy[J].Cell Res,2017,27(1):109-118.
[8] CHAUDHARY B,ELKORD E.Regulatory T Cells in the tumor microenvironment and cancer progression:role and therapeutic targeting[J].Vaccines(Basel),2016,4(3):E28.
[9] CARIANI E,MISSALE G.Immune landscape of hepatocellular carcinoma microenvironment:implications for prognosis and therapeutic applications[J].Liver Int,2019,39(9):1608-1621.
[10] GAO Q,QIU SJ,FAN J,et al.Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection[J].J Clin Oncol,2007,25(18):2586-2593.
[11] ZHENG C,ZHENG L,YOO JK,et al.Landscape of infiltrating t cells in liver cancer revealed by single-cell sequencing[J].Cell,2017,169(7):1342-1356,e1316.
[12] SPRINZL MF,GALLE PR.Immune control in hepatocellular carcinoma development and progression:role of stromal cells[J].Semin Liver Dis,2014,34(4):376-388.
[13] CHEN X,DU Y,HUANG Z.CD4+ CD25+ Treg derived from hepatocellular carcinoma mice inhibits tumor immunity[J].Immunol Lett,2012,148(1):83-89.
[14] KALATHIL S,LUGADE AA,MILLER A,et al.Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality[J].Cancer Res,2013,73(8):2435-2444.
[15] CAI XY,NI XC,YI Y,et al.Overexpression of CD39 in hepatocellular carcinoma is an independent indicator of poor outcome after radical resection[J].Medicine,2016,95(40):e4989.
[16] KORANGY F,HÖCHST B,MANNS MP,et al.Immunotherapy of hepatocellular carcinoma[J]. Exp Rev Gastroenterol Hepatol,2010,4(3):345-353.
[17] VEGLIA F,PEREGO M,GABRILOVICH D.Myeloid-derived suppressor cells coming of age[J].Nat Immunol,2018,19(2):108-119.
[18] LI X,YAO W,YUAN Y,et al.Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma[J].Gut,2017,66(1):157-167.
[19] GAO XH,TIAN L,WU J,et al.Circulating CD14 HLA-DR myeloid-derived suppressor cells predicted early recurrence of hepatocellular carcinoma after surgery[J].Hepatol Res,2017,47(10):1061-1071.
[20] MIZUKOSHI E,YAMASHITA T,ARAI K,et al.Myeloid-derived suppressor cells correlate with patient outcomes in hepatic arterial infusion chemotherapy for hepatocellular carcinoma[J].Cancer Immunol Immunother,2016,65(6):715-725.
[21] DRAGHICIU O,LUBBERS J,NIJMAN HW,et al.Myeloid derived suppressor cells-An overview of combat strategies to increase immunotherapy efficacy[J].Oncoimmunology,2015,4(1):e954829.
[22] LU T,GABRILOVICH DI.Molecular pathways:tumor-infiltrating myeloid cells and reactive oxygen species in regulation of tumor microenvironment[J].Clin Cancer Res,2012,18(18):4877-4882.
[23] KONDO Y,SHIMOSEGAWA T.Significant roles of regulatory T cells and myeloid derived suppressor cells in hepatitis B virus persistent infection and hepatitis B virus-related HCCs[J].Int J Mol Sci,2015,16(2):3307-3322.
[24] ILKOVITCH D,LOPEZ DM.The liver is a site for tumor-induced myeloid-derived suppressor cell accumulation and immunosuppression[J].Cancer Res,2009,69(13):5514-5521.
[25] HOECHST B,VOIGTLAENDER T,ORMANDY L,et al.Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 Receptor[J].Hepatology,2009,50(3):799-807.
[26] DOU L,ONO Y,CHEN YF,et al.Hepatic dendritic cells,the tolerogenic liver environment,and liver disease[J].Semin liver Dis,2018,38(2):170-180.
[27] REIZIS B,BUNIN A,GHOSH HS,et al.Plasmacytoid dendritic cells:recent progress and open questions[J].Ann Rev Immunol,2011,29:163-183.
[28] GUILLIAMS M,GINHOUX F,JAKUBZICK C,et al.Dendritic cells,monocytes and macrophages:a unified nomenclature based on ontogeny[J].Nat Rev Immunol,2014,14(8):571-578.
[29] SCHLITZER A,SIVAKAMASUNDARI V,CHEN JM,et al.Identification of cDC1-and cDC2-committed DC progenitors reveals early lineage priming at the common DC progenitor stage in the bone marrow[J].Nat Immunol,2015,16(7):718-728.
[30] MILDNER A,JUNG S.Development and function of dendritic cell subsets[J].Immunity,2014,40(5):642-656.
[31] MURPHY TL,GRAJALES-REYES GE,WU XD,et al.Transcriptional control of dendritic cell development[J].Ann Rev Immunol,2016,34:93-119.
[32] SEGURA E,TOUZOT M,BOHINEUST A,et al.Human inflammatory dendritic cells induce th17 cell differentiation[J].Immunity,2013,38(2):336-348.
[33] CONEJO-GARCIA JR,RUTKOWSKI MR,CUBILLOS-RUIZ JR.State-of-the-art of regulatory dendritic cells in cancer[J].Pharmacol Ther,2016,164:97-104.
[34] GENTLES AJ,NEWMAN AM,LIU CL,et al.The prognostic landscape of genes and infiltrating immune cells across human cancers[J].Nat Med,2015,21(8):938-945.
[35] ZHONG M,ZHONG C,CUI W,et al.Induction of tolerogenic dendritic cells by activated TGF-β/Akt/Smad2 signaling in RIG-I-deficient stemness-high human liver cancer cells[J]. BMC Cancer,2019,19(1):439.
[36] MIZUKOSHI E,KANEKO S.Immune cell therapy for hepatocellular carcinoma[J].J Hematol Oncol,2019,12(1):52.
[37] OUYANG FZ,WU RQ,WEI Y,et al.Dendritic cell-elicited B-cell activation fosters immune privilege via IL-10 signals in hepatocellular carcinoma[J].Nat Commun,2016,7:13453.
[38] PEDROZA-GONZALEZ A,ZHOU GY,VARGAS-MENDEZ E,et al.Tumor-infiltrating plasmacytoid dendritic cells promote immunosuppression by Tr1 cells in human liver tumors[J].Oncoimmunology,2015,4(6):e1008335.
[39] SONG S,YUAN P,WU H,et al.Dendritic cells with an increased PD-L1 by TGF-β induce T cell anergy for the cytotoxicity of hepatocellular carcinoma cells[J].Int Immunopharmacol,2014,20(1):117-123.
[40] ZHOU G,SPRENGERS D,BOOR PPC,et al.Antibodies Against immune checkpoint molecules restore functions of tumor-infiltrating t cells in hepatocellular carcinomas[J]. Gastroenterology,2017,153(4):1107-1119,e1110.
[41] CHENG JT,DENG YN,YI HM,et al.Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation[J]. Oncogenesis,2016,5:e198.
[42] LIU Y,CAO XT.The origin and function of tumor-associated macrophages[J].Cell Mol Immunol,2015,12(1):1-4.
[43] CAPECE D,FISCHIETTI M,VERZELLA D,et al.The inflammatory microenvironment in hepatocellular carcinoma:a pivotal role for tumor-associated macrophages[J].Biomed Res Int,2013,2013:187204.
[44] TAKAI H,ASHIHARA M,ISHIGURO T,et al.Involvement of glypican-3 in the recruitment of M2-polarized tumor-associated macrophages in hepatocellular carcinoma[J].Cancer Biol Ther,2009,8(24):2329-2338.
[45] YEUNG OW,LO CM,LING CC,et al.Alternatively activated(M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma[J].J Hepatol,2015,62(3):607-616.
[46] DONG PP,MA LJ,LIU LZ,et al.CD86(+)/CD206(+),diametrically polarized tumor-associated macrophages,predict hepatocellular carcinoma patient prognosis[J].Int J Mol Sci,2016,17(3):320.
[47] KUANG DM,ZHAO QY,PENG C,et al.Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1[J].J Exp Med,2009,206(6):1327-1337.
[48] GORDON SR,AUTE RLM,DULKEN BW,et al.PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity[J].Nature,2017,545(7655):495-499.
[49] ZHOU J,DING T,PAN W,et al.Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients[J]. Int J Cancer,2009,125(7):1640-1648.
[50] LI TJ,YANG Y,HUA XF,et al.Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO[J].Cancer Lett,2012,318(2):154-161.
[51] DENG Y,CHENG J,FU B,et al.Hepatic carcinoma-associated fibroblasts enhance immune suppression by facilitating the generation of myeloid-derived suppressor cells[J]. Oncogene,2017,36(8):1090-1101.
[52] CHENG Y,LI H,DENG Y,et al.Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma[J].Cell Death Dis,2018,9(4):422.
[53] ZHAO W,ZHANG L,XU Y,et al.Hepatic stellate cells promote tumor progression by enhancement of immunosuppressive cells in an orthotopic liver tumor mouse model[J]. Lab Invest,2014,94(2):182-191.
[54] XU YP,ZHAO WX,XU JF,et al.Activated hepatic stellate cells promote liver cancer by induction of myeloid-derived suppressor cells through cyclooxygenase-2[J].Oncotarget,2016,7(8):8866-8878.
[55] CHEN YC,HUANG YH,REIBERGER T,et al.Differential Effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 Alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice[J].Hepatology,2014,59(4):1435-1447.
[56] DAVID CJ,MASSAGUÉ J.Contextual determinants of TGFβ action in development,immunity and cancer[J].Nat Rev Mol Cell Biol,2018,19(7):419-435.
[57] HAMMERICH L,TACKE F.Interleukins in chronic liver disease:lessons learned from experimental mouse models[J].Clin Exp Gastroenterol,2014,7:297-306.
[58] RAI V,ABDO J,ALSUWAIDAN AN,et al.Cellular and molecular targets for the immunotherapy of hepatocellular carcinoma[J].Mol Cell Biochem,2017,437(1-2):13-36.
[59] MUNN DH,MELLOR AL.IDO in the tumor microenvironment:inflammation,counter-regulation,and tolerance[J].Trends Immunol,2016,37(3):193-207.
[60] HAN YM,CHEN ZB,YANG Y,et al.Human CD14(+)CTLA-4(+) regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and Indoleamine-2,3-dioxygenase production in hepatocellular carcinoma[J].Hepatology,2014,59(2):567-579.
[61] ASGHAR K,FAROOQ A,ZULFIQAR B,et al.Indoleamine 2,3-dioxygenase:As a potential prognostic marker and immunotherapeutic target for hepatocellular carcinoma[J].World K Gastroenterol,2017,23(13):2286-2293.
[62] HOECHST B,ORMANDY LA,BALLMAIER M,et al.A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells[J].Gastroenterology,2008,135(1):234-243.
[63] KANG FB,WANG L,LI D,et al.Hepatocellular carcinomas promote tumor-associated macrophage M2-polarization via increased B7-H3 expression[J].Oncol Rep,2015,33(1):274-282.
[64] ZAREK PE,HUANG CT,LUTZ ER,et al.A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells[J]. Blood,2008,111(1):251-259.
[65] ZAROUR HM.Reversing T-cell dysfunction and exhaustion in cancer[J].Clin Cancer Res,2016,22(8):1856-1864.
[66] DYCK L,MILLS KHG.Immune checkpoints and their inhibition in cancer and infectious diseases[J].Eur J Immunol,2017,47(5):765-779.
[67] HATO T,GOYAL L,GRETEN TF,et al.Immune checkpoint blockade in hepatocellular carcinoma:current progress and future directions[J].Hepatology,2014,60(5):1776-1782.
[68] IHLING C,NAUGHTON B,ZHANG Y,et al.Observationalstudy of PD-L1,TGF-β,and immune cell infiltrates in hepatocellular carcinoma[J].Front Med,2019,6:15.
[69] 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[J].Lancet,2017,389(10088):2492-2502.
[70] EL-DIKA I,KHALIL DN,ABOU-ALFA GK.Immune checkpoint inhibitors for hepatocellular carcinoma[J].Cancer,2019,125(19):3312-3319.
[71] ZHU AX,FINN RS,EDELINE J,et al.Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenibofNOTE-224):a non-randomised,open-label phase 2 trial[J].Lancet Oncol,2018,19(7):940-952.
[72] KUDO M.Immuno-Oncology in Hepatocellular Carcinoma:2017 Update[J].Oncology,2017,93(Suppl 1):147-159.
[73] RAMAGOPAL UA,LIU WF,GARRETT-THOMSON SC,et al.Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab[J].Proc Natl Acad Sci U S A,2017,114(21):E4223-E4232.
[74] CHEN X,DU Y,HU QQ,et al.Tumor-derived CD4+ CD25+ regulatory T cells inhibit dendritic cells function by CTLA-4[J].Pathol Res Prac,2017,213(3):245-249.
[75] MIZUKOSHI E,NAKAMOTO Y,ARAI K,et al.Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma[J]. Hepatology,2011,53(4):1206-1216.
[76] LI H,WU K,TAO KX,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[J].Hepatology,2012,56(4):1342-1351.
[77] YAN WJ,LIU X,MA HX,et al.Tim-3 fosters HCC development by enhancing TGF-beta-mediated alternative activation of macrophages[J].Gut,2015,64(10):1593-1604.
[78] LI FJ,ZHANG Y,JIN GX,et al.Expression of LAG-3 is coincident with the impaired effector function of HBV-specific CD8(+) T cell in HCC patients[J].Immunol Lett,2013,150(1-2):116-122.
[79] MATSUDA Y,YAMAGIWA Y,FUKUSHIMA K,et al.Expression of galectin-3 involved in prognosis of patients with hepatocellular carcinoma[J].Hepatol Res,2008,38(11):1098-1111.
[80] HOKUTO D,SHO M,YAMATO I,et al.Clinical impact of herpesvirus entry mediator expression in human hepatocellular carcinoma[J].Eur J Cancer,2015,51(2):157-165.