372
Views
9
CrossRef citations to date
0
Altmetric
Reviews

Spontaneous and therapeutic immune responses in hepatocellular carcinoma: implications for current and future immunotherapies

References

  • Fu J, Xu D, Liu Z et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132(7), 2328–2339 (2007).
  • Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Ann. Rev. Immunol. 30, 531–564 (2012).
  • Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res. 65(6), 2457–2464 (2005).
  • Chen KJ, Lin SZ, Zhou L et al. Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis. PLoS ONE, 6(9), e24671 (2011).
  • Chen KJ, Zhou L, Xie HY, Ahmed TE, Feng XW, Zheng SS. Intratumoral regulatory T cells alone or in combination with cytotoxic T cells predict prognosis of hepatocellular carcinoma after resection. Med. Oncol. 29(3), 1817–1826 (2012).
  • Huang Y, Wang FM, Wang T et al. Tumor-infiltrating FoxP3+ Tregs and CD8+ T cells affect the prognosis of hepatocellular carcinoma patients. Digestion 86(4), 329–337 (2012).
  • Unitt E, Rushbrook SM, Marshall A et al. Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology 41(4), 722–730 (2005).
  • Pedroza-Gonzalez A, Verhoef C, Ijzermans JN et al. Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer. Hepatology 57(1), 183–194 (2013).
  • Greten TF, Ormandy LA, Fikuart A et al. Low-dose cyclophosphamide treatment impairs regulatory T cells and unmasks AFP-specific CD4+ T-cell responses in patients with advanced HCC. J. Immunother 33(2), 211–218 (2010).
  • Zhang HH, Mei MH, Fei R et al. Regulatory T cell depletion enhances tumor specific CD8 T-cell responses, elicited by tumor antigen NY-ESO-1b in hepatocellular carcinoma patients, in vitro. Inter. J. Oncol. 36(4), 841–848 (2010).
  • Haile LA, Greten TF, Korangy F. Immune suppression: the hallmark of myeloid derived suppressor cells. Immunol. Invest. 41(6–7), 581–594 (2012).
  • 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. Gastroenterology 135(1), 234–243 (2008).
  • 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. Hepatology 50(3), 799–807 (2009).
  • Vincent J, Mignot G, Chalmin F et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 70(8), 3052–3061 (2010).
  • Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD. Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Inter. Immunopharmacol. 9(7–8), 900–909 (2009).
  • Zhao Q, Xiao X, Wu Y et al. Interleukin-17-educated monocytes suppress cytotoxic T-cell function through B7-H1 in hepatocellular carcinoma patients. Eur. J. Immunol. 41(8), 2314–2322 (2011).
  • Kuang DM, Peng C, Zhao Q, Wu Y, Chen MS, Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology 51(1), 154–164 (2010).
  • Zhao F, Hoechst B, Gamrekelashvili J et al. Human CCR4+ CCR6+ Th17 cells suppress autologous CD8+ T cell responses. J. Immunol. 188(12), 6055–6062 (2012).
  • Liao R, Sun J, Wu H et al. High expression of IL-17 and IL-17RE associate with poor prognosis of hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 32, 3 (2013).
  • Ohki S, Shibata M, Gonda K et al. Circulating myeloid-derived suppressor cells are increased and correlate to immune suppression, inflammation and hypoproteinemia in patients with cancer. Oncol. Report. 28(2), 453–458 (2012).
  • Zhang JP, Yan J, Xu J et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J. Hepatol. 50(5), 980–989 (2009).
  • Li YW, Qiu SJ, Fan J et al. Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J. Hepatol. 54(3), 497–505 (2011).
  • Gomez D, Farid S, Malik HZ et al. Preoperative neutrophil-to-lymphocyte ratio as a prognostic predictor after curative resection for hepatocellular carcinoma. World J. Surg. 32(8), 1757–1762 (2008).
  • Liao Y, Wang B, Huang ZL et al. Increased circulating Th17 cells after transarterial chemoembolization correlate with improved survival in stage III hepatocellular carcinoma: a prospective study. PLoS ONE 8(4), e60444 (2013).
  • Schurich A, Berg M, Stabenow D et al. Dynamic regulation of CD8 T cell tolerance induction by liver sinusoidal endothelial cells. J. Immunol. 184(8), 4107–4114 (2010).
  • Bottcher JP, Schanz O, Wohlleber D et al. Liver-primed memory T cells generated under noninflammatory conditions provide anti-infectious immunity. Cell Rep. 3(3), 779–795 (2013).
  • Zeng Z, Yao W, Xu X et al. Hepatocellular carcinoma cells deteriorate the biophysical properties of dendritic cells. Cell Biochem. Biophy. 55(1), 33–43 (2009).
  • Xia Y, Chen R, Ye SL, Sun R, Chen J, Zhao Y. Inhibition of T-cell responses by intratumoral hepatic stellate cells contribute to migration and invasion of hepatocellular carcinoma. Clin. Exp. Metastasis 28(7), 661–674 (2011).
  • Zhao W, Su W, Kuang P et al. The role of hepatic stellate cells in the regulation of T-cell function and the promotion of hepatocellular carcinoma. Int. J. Oncol. 41(2), 457–464 (2012).
  • Mizukoshi E, Nakamoto Y, Arai K et al. Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma. Hepatology 53(4), 1206–1216 (2011).
  • Mizukoshi E, Nakamoto Y, Marukawa Y et al. Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma. Hepatology 43(6), 1284–1294 (2006).
  • Thimme R, Neagu M, Boettler T et al. Comprehensive analysis of the alpha-fetoprotein-specific CD8+ T cell responses in patients with hepatocellular carcinoma. Hepatology 48(6), 1821–1833 (2008).
  • Behboudi S, Boswell S, Williams R. Cell-mediated immune responses to alpha-fetoprotein and other antigens in hepatocellular carcinoma. Liver Int. 30(4), 521–526 (2010).
  • Butterfield LH, Ribas A, Potter DM, Economou JS. Spontaneous and vaccine induced AFP-specific T cell phenotypes in subjects with AFP-positive hepatocellular cancer. Cancer Immunol. Immunother. 56(12), 1931–1943 (2007).
  • Mizukoshi E, Nakamoto Y, Tsuji H, Yamashita T, Kaneko S. Identification of alpha-fetoprotein-derived peptides recognized by cytotoxic T lymphocytes in HLA-A24+ patients with hepatocellular carcinoma. Int. J. Cancer 118(5), 1194–1204 (2006).
  • Bei R, Budillon A, Reale MG et al. Cryptic epitopes on alpha-fetoprotein induce spontaneous immune responses in hepatocellular carcinoma, liver cirrhosis, and chronic hepatitis patients. Cancer Res. 59(21), 5471–5474 (1999).
  • Bei R, Mizejewski GJ. Alpha fetoprotein is more than a hepatocellular cancer biomarker: from spontaneous immune response in cancer patients to the development of an AFP-based cancer vaccine. Curr. Mol. Med. 11(7), 564–581 (2011).
  • Evdokimova VN, Liu Y, Potter DM, Butterfield LH. AFP-specific CD4+ helper T-cell responses in healthy donors and HCC patients. J. Immunother. 30(4), 425–437 (2007).
  • Witkowski M, Spangenberg HC, Neumann-Haefelin C et al. Lack of ex vivo peripheral and intrahepatic alpha-fetoprotein-specific CD4+ responses in hepatocellular carcinoma. Int. J. Cancer 129(9), 2171–2182 (2011).
  • Motomura Y, Ikuta Y, Kuronuma T et al. HLA-A2 and -A24-restricted glypican-3-derived peptide vaccine induces specific CTLs: preclinical study using mice. Int. J. Oncol. 32(5), 985–990 (2008).
  • Shang XY, Chen HS, Zhang HG et al. The spontaneous CD8+ T-cell response to HLA-A2-restricted NY-ESO-1b peptide in hepatocellular carcinoma patients. Clin. Cancer Res. 10(20), 6946–6955 (2004).
  • Korangy F, Ormandy LA, Bleck JS et al. Spontaneous tumor-specific humoral and cellular immune responses to NY-ESO-1 in hepatocellular carcinoma. Clin. Cancer Res. 10(13), 4332–4341 (2004).
  • Zhang HG, Chen HS, Peng JR et al. Specific CD8(+)T cell responses to HLA-A2 restricted MAGE-A3 p271–279 peptide in hepatocellular carcinoma patients without vaccination. Cancer Immunol. Immunother. 56(12), 1945–1954 (2007).
  • Bricard G, Bouzourene H, Martinet O et al. Naturally acquired MAGE-A10- and SSX-2-specific CD8+ T cell responses in patients with hepatocellular carcinoma. J. Immunol. 174(3), 1709–1716 (2005).
  • Song MH, Choi KU, Shin DH, Lee CH, Lee SY. Identification of the cancer/testis antigens AKAP3 and CTp11 by SEREX in hepatocellular carcinoma. Oncol. Rep. 28(5), 1792–1798 (2012).
  • Shen H, Shao HW, Chen XH et al. Identification of a novel HLA-A2-restricted mutated Survivin epitope and induction of specific anti-HCC CTLs that could effectively cross-recognize wild-type Survivin antigen. Cancer Immunol. Immunother. 62(2), 393–403 (2013).
  • Mizukoshi E, Fushimi K, Arai K, Yamashita T, Honda M, Kaneko S. Expression of chondroitin-glucuronate C5-epimerase and cellular immune responses in patients with hepatocellular carcinoma. Liver Int. 32(10), 1516–1526 (2012).
  • Dong XY, Yang XA, Wang YD, Chen WF. Zinc-finger protein ZNF165 is a novel cancer-testis antigen capable of eliciting antibody response in hepatocellular carcinoma patients. Br. J. Cancer 91(8), 1566–1570 (2004).
  • Shimoda M, Tomimaru Y, Charpentier KP, Safran H, Carlson RI, Wands J. Tumor progression-related transmembrane protein aspartate-beta-hydroxylase is a target for immunotherapy of hepatocellular carcinoma. J. Hepatol. 56(5), 1129–1135 (2012).
  • Stauffer JK, Scarzello AJ, Jiang Q, Wiltrout RH. Chronic inflammation, immune escape, and oncogenesis in the liver: a unique neighborhood for novel intersections. Hepatology 56(4), 1567–1574 (2012).
  • He G, Karin M. NF-kappaB and STAT3 - key players in liver inflammation and cancer. Cell Res. 21(1), 159–168 (2011).
  • Wong VW, Yu J, Cheng AS et al. High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B. Int. J. Cancer 124(12), 2766–2770 (2009).
  • Bettermann K, Vucur M, Haybaeck J et al. TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell 17(5), 481–496 (2010).
  • Sakurai T, He G, Matsuzawa A et al. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14(2), 156–165 (2008).
  • Schneider C, Teufel A, Yevsa T et al. Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer. Gut 61(12), 1733–1743 (2012).
  • Nakamoto Y, Guidotti LG, Kuhlen CV, Fowler P, Chisari FV. Immune pathogenesis of hepatocellular carcinoma. J. Exp. Med. 188(2), 341–350 (1998).
  • Haybaeck J, Zeller N, Wolf MJ et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 16(4), 295–308 (2009).
  • Unitt E, Marshall A, Gelson W et al. Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J. Hepatol. 45(2), 246–253 (2006).
  • Flecken T, Schmidt N, Hild S et al. Immunodominance and functional alterations of tumor-associated antigen-specific CD8 T-cell responses in hepatocellular carcinoma. Hepatology (2013) (Epub ahead of print).
  • Gao B, Radaeva S, Park O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J. Leuk. Biol. 86(3), 513–528 (2009).
  • Subleski JJ, Jiang Q, Weiss JM, Wiltrout RH. The split personality of NKT cells in malignancy, autoimmune and allergic disorders. Immunotherapy 3(10), 1167–1184 (2011).
  • Doi H, Iyer TK, Carpenter E et al. Dysfunctional B-cell activation in cirrhosis resulting from hepatitis C infection associated with disappearance of CD27-positive B-cell population. Hepatology 55(3), 709–719 (2012).
  • de Visser KE, Korets LV, Coussens LM. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7(5), 411–423 (2005).
  • Kobayashi N, Hiraoka N, Yamagami W et al. FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin. Cancer Res. 13(3), 902–911 (2007).
  • Hu CE, Gan J, Zhang RD, Cheng YR, Huang GJ. Up-regulated myeloid-derived suppressor cell contributes to hepatocellular carcinoma development by impairing dendritic cell function. Scand. J. Gastroenterol. 46(2), 156–164 (2011).
  • Kang TW, Yevsa T, Woller N et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479(7374), 547–551 (2011).
  • Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Ann. Rev. Immunol. 29, 235–271 (2011).
  • Lin H, Yan J, Wang Z et al. Loss of immunity-supported senescence enhances susceptibility to hepatocellular carcinogenesis and progression in Toll-like receptor 2-deficient mice. Hepatology 57(1), 171–182 (2013).
  • Kaposi-Novak P, Libbrecht L, Woo HG et al. Central role of c-Myc during malignant conversion in human hepatocarcinogenesis. Cancer Res. 69(7), 2775–2782 (2009).
  • Wu CH, van Riggelen J, Yetil A, Fan AC, Bachireddy P, Felsher DW. Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proc. Natl Acad. Sci. USA 104(32), 13028–13033 (2007).
  • Xue W, Zender L, Miething C et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445(7128), 656–660 (2007).
  • Braumuller H, Wieder T, Brenner E et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 494(7437), 361–365 (2013).
  • Kumar V, Kato N, Urabe Y et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat. Genet. 43(5), 455–458 (2011).
  • Butterfield LH, Koh A, Meng W et al. Generation of human T-cell responses to an HLA-A2.1-restricted peptide epitope derived from alpha-fetoprotein. Cancer Res. 59(13), 3134–3142 (1999).
  • Gehring AJ, Ho ZZ, Tan AT et al. Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma. Gastroenterology 137(2), 682–690 (2009).
  • Huz JI, Melis M, Sarpel U. Spontaneous regression of hepatocellular carcinoma is most often associated with tumour hypoxia or a systemic inflammatory response. HPB (Oxford) 14(8), 500–505 (2012).
  • Storey RE, Huerta AL, Khan A, Laber DA. Spontaneous complete regression of hepatocellular carcinoma. Med. Oncol. 28(4), 948–950 (2011).
  • Blondon H, Fritsch L, Cherqui D. Two cases of spontaneous regression of multicentric hepatocellular carcinoma after intraperitoneal rupture: possible role of immune mechanisms. Eur. J. Gastroenterol. Hepatol. 16(12), 1355–1359 (2004).
  • Zerbini A, Pilli M, Soliani P et al. Ex vivo characterization of tumor-derived melanoma antigen encoding gene-specific CD8+cells in patients with hepatocellular carcinoma. J. Hepatol. 40(1), 102–109 (2004).
  • Harimoto N, Shirabe K, Kajiyama K et al. Spontaneous regression of multiple pulmonary recurrences of hepatocellular carcinoma after hepatectomy: report of a case. Surg. Today 42(5), 475–478 (2012).
  • Mizukoshi E, Yamashita T, Arai K et al. Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology 57(4), 1448–1457 (2013).
  • Xia JZ, Xie FL, Ran LF, Xie XP, Fan YM, Wu F. High-intensity focused ultrasound tumor ablation activates autologous tumor-specific cytotoxic T lymphocytes. Ultrasound Med. Biol. 38(8), 1363–1371 (2012).
  • Zerbini A, Pilli M, Fagnoni F et al. Increased immunostimulatory activity conferred to antigen-presenting cells by exposure to antigen extract from hepatocellular carcinoma after radiofrequency thermal ablation. J. Immunother. 31(3), 271–282 (2008).
  • Zerbini A, Pilli M, Penna A et al. Radiofrequency thermal ablation of hepatocellular carcinoma liver nodules can activate and enhance tumor-specific T-cell responses. Cancer Res. 66(2), 1139–1146 (2006).
  • Ali MY, Grimm CF, Ritter M et al. Activation of dendritic cells by local ablation of hepatocellular carcinoma. J. Hepatol. 43(5), 817–822 (2005).
  • Nobuoka D, Motomura Y, Shirakawa H et al. Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes. Int. J. Oncol. 40(1), 63–70 (2012).
  • Ayaru L, Pereira SP, Alisa A et al. Unmasking of alpha-fetoprotein-specific CD4(+) T cell responses in hepatocellular carcinoma patients undergoing embolization. J. Immunol. 178(3), 1914–1922 (2007).
  • Edwards JP, Emens LA. The multikinase inhibitor sorafenib reverses the suppression of IL-12 and enhancement of IL-10 by PGE(2) in murine macrophages. Int. Immunopharmacol. 10(10), 1220–1228 (2010).
  • Chen ML, Yan BS, Lu WC et al. Sorafenib relieves cell-intrinsic and cell-extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity. Int. J. Cancer (2013) (Epub ahead of print).
  • Sprinzl MF, Reisinger F, Puschnik A et al. Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells. Hepatology 57(6), 2358–2368 (2013).
  • Wang Q, Yu T, Yuan Y et al. Sorafenib reduces hepatic infiltrated regulatory T cells in hepatocellular carcinoma patients by suppressing TGF-beta signal. J. Surg. Oncol. 107(4), 422–427 (2013).
  • Cao M, Xu Y, Youn JI et al. Kinase inhibitor Sorafenib modulates immunosuppressive cell populations in a murine liver cancer model. Lab. Invest. 91(4), 598–608 (2011).
  • Cabrera R, Ararat M, Xu Y et al. Immune modulation of effector CD4+ and regulatory T cell function by sorafenib in patients with hepatocellular carcinoma. Cancer Immunol. Immunother. 62(4), 737–746 (2013).
  • Nagai H, Mukozu T, Matsui D et al. Sorafenib prevents escape from host immunity in liver cirrhosis patients with advanced hepatocellular carcinoma. Clin. Dev. Immunol. 2012, 607851 (2012).
  • Hipp MM, Hilf N, Walter S et al. Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. Blood 111(12), 5610–5620 (2008).
  • Weng DS, Zhou J, Zhou QM et al. Minimally invasive treatment combined with cytokine-induced killer cells therapy lower the short-term recurrence rates of hepatocellular carcinomas. J. Immunother. 31(1), 63–71 (2008).
  • Takayama T, Sekine T, Makuuchi M et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 356(9232), 802–807 (2000).
  • Kuang M, Peng BG, Lu MD et al. Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma. Clin. Cancer Res. 10(5), 1574–1579 (2004).
  • Pan K, Li YQ, Wang W et al. The efficacy of cytokine-induced killer cell infusion as an adjuvant therapy for postoperative hepatocellular carcinoma patients. Ann. Surg. Oncol. (2013) (Epub ahead of print).
  • Zhong JH, Li H, Li LQ et al. Adjuvant therapy options following curative treatment of hepatocellular carcinoma: a systematic review of randomized trials. Eur. J. Surg. Oncol. 38(4), 286–295 (2012).
  • Inui T, Ohno T. Autologous formalin-fixed tumor vaccine suppressed re-recurrence of HCV-related hepatocellular carcinoma following 29 unsuccessful treatments with extensive conventional therapy: a case report. World J. Surg. Oncol. 10, 144 (2012).
  • Sun K, Wang L, Zhang Y. Dendritic cell as therapeutic vaccines against tumors and its role in therapy for hepatocellular carcinoma. Cell. Mol. Immunol. 3(3), 197–203 (2006).
  • El Ansary M, Mogawer S, Elhamid SA et al. Immunotherapy by autologous dendritic cell vaccine in patients with advanced HCC. J. Cancer Res. Clin. Oncol. 139(1), 39–48 (2013).
  • Palmer DH, Midgley RS, Mirza N et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 49(1), 124–132 (2009).
  • Lee WC, Wang HC, Hung CF, Huang PF, Lia CR, Chen MF. Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: a clinical trial. J. Immunother. 28(5), 496–504 (2005).
  • Ladhams A, Schmidt C, Sing G et al. Treatment of non-resectable hepatocellular carcinoma with autologous tumor-pulsed dendritic cells. J. Gastroenterol. Hepatol. 17(8), 889–896 (2002).
  • Nakamoto Y, Mizukoshi E, Tsuji H et al. Combined therapy of transcatheter hepatic arterial embolization with intratumoral dendritic cell infusion for hepatocellular carcinoma: clinical safety. Clin. Exp. Immunol. 147(2), 296–305 (2007).
  • Mizukoshi E, Nakamoto Y, Arai K et al. Enhancement of tumor-specific T-cell responses by transcatheter arterial embolization with dendritic cell infusion for hepatocellular carcinoma. Int. J. Cancer 126(9), 2164–2174 (2010).
  • Zhang HM, Zhang LW, Liu WC, Cheng J, Si XM, Ren J. Comparative analysis of DC fused with tumor cells or transfected with tumor total RNA as potential cancer vaccines against hepatocellular carcinoma. Cytotherapy 8(6), 580–588 (2006).
  • Zhang H, Zheng SS, Jiang GP, Wu LH, Zhu F, Yang ZL. Antitumor effect of immunization with fusion of dendritic cells and hepatocellular carcinoma cells in mice. Hepatobiliary Pancreat. Dis. Int. 3(2), 235–240 (2004).
  • Vollmer CM Jr, Eilber FC, Butterfield LH et al. Alpha-fetoprotein-specific genetic immunotherapy for hepatocellular carcinoma. Cancer Res. 59(13), 3064–3067 (1999).
  • Zhang W, Liu J, Wu Y et al. Immunotherapy of hepatocellular carcinoma with a vaccine based on xenogeneic homologous alpha fetoprotein in mice. Biochem. Biophys. Res. Commun. 376(1), 10–14 (2008).
  • Sawada Y, Yoshikawa T, Nobuoka D et al. Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival. Clin. Cancer Res. 18(13), 3686–3696 (2012).
  • Zhu AX, Gold PJ, El-Khoueiry AB et al. First-in-man phase I study of GC33, a novel recombinant humanized antibody against glypican-3, in patients with advanced hepatocellular carcinoma. Clin. Cancer Res. 19(4), 920–928 (2013).
  • Qiu Y, Xu MB, Yun MM et al. Hepatocellular carcinoma-specific immunotherapy with synthesized alpha1,3- galactosyl epitope-pulsed dendritic cells and cytokine-induced killer cells. World J. Gastroenterol. 17(48), 5260–5266 (2011).
  • Greten TF, Forner A, Korangy F et al. A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma. BMC Cancer 10, 209 (2010).
  • Zhang XM, Zhang YF, Huang Y et al. The anti-tumor immune response induced by a combination of MAGE-3/MAGE-n-derived peptides. Oncol. Rep. 20(1), 245–252 (2008).
  • Wang XH, Qin Y, Hu MH, Xie Y. Dendritic cells pulsed with gp96-peptide complexes derived from human hepatocellular carcinoma (HCC) induce specific cytotoxic T lymphocytes. Cancer Immunol. Immunother. 54(10), 971–980 (2005).
  • Ren W, Strube R, Zhang X, Chen SY, Huang XF. Potent tumor-specific immunity induced by an in vivo heat shock protein-suicide gene-based tumor vaccine. Cancer Res. 64(18), 6645–6651 (2004).
  • Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363(8), 711–723 (2010).
  • Shi F, Shi M, Zeng Z et al. PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int. J. Cancer 128(4), 887–896 (2011).
  • Hsu PN, Yang TC, Kao JT et al. Increased PD-1 and decreased CD28 expression in chronic hepatitis B patients with advanced hepatocellular carcinoma. Liver Int. 30(9), 1379–1386 (2010).
  • Wang BJ, Bao JJ, Wang JZ et al. Immunostaining of PD-1/PD-Ls in liver tissues of patients with hepatitis and hepatocellular carcinoma. World J. Gastroenterol. 17(28), 3322–3329 (2011).
  • Kalathil S, Lugade AA, Miller A, Iyer R, Thanavala Y. 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. Cancer Res. 73(8), 2435–2444 (2013).
  • Hu L, Liu J, Chen X et al. CTLA-4 gene polymorphism +49 A/G contributes to genetic susceptibility to two infection-related cancers-hepatocellular carcinoma and cervical cancer. Hum. Immunol. 71(9), 888–891 (2010).
  • Willimsky G, Schmidt K, Loddenkemper C, Gellermann J, Blankenstein T. Virus-induced hepatocellular carcinomas cause antigen-specific local tolerance. J. Clin. Invest. 123(3), 1032–1043 (2013).
  • Sangro B, Gomez-Martin C, de la Mata M et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J. Hepatol. 59(1), 81–88 (2013).
  • 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. 150(1–2), 116–122 (2013).
  • Li H, Wu K, Tao K et al. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 56(4), 1342–1351 (2012).
  • Senzer NN, Kaufman HL, Amatruda T et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J. Clin. Oncol. 27(34), 5763–5771 (2009).
  • Heo J, Reid T, Ruo L et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat. Med. 19(3), 329–336 (2013).
  • Butterfield LH, Ribas A, Dissette VB et al. A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin. Cancer Res. 12(9), 2817–2825 (2006).
  • Butterfield LH, Meng WS, Koh A et al. T cell responses to HLA-A*0201-restricted peptides derived from human alpha fetoprotein. J. Immunol. 166(8), 5300–5308 (2001).
  • Han Y, Chen Z, Yang Y et al. Human CD14 CTLA-4 regulatory dendritic cells suppress T cell response via CTLA-4-dependent IL-10 and IDO production in hepatocellular carcinoma. Hepatology (2013) (Epub ahead of print).
  • Gao Q, Wang XY, Qiu SJ et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin. Cancer Res. 15(3), 971–979 (2009).
  • Yan J, Zhang Y, Zhang JP, Liang J, Li L, Zheng L. Tim-3 expression defines regulatory T cells in human tumors. PLoS ONE 8(3), e58006 (2013).
  • Li Z, Liu Z, Zhang G et al. TIM3 gene polymorphisms in patients with chronic hepatitis B virus infection: impact on disease susceptibility and hepatocellular carcinoma traits. Tissue Antigens 80(2), 151–157 (2012).
  • Tatsumi T, Takehara T, Katayama K et al. Expression of costimulatory molecules B7–1 (CD80) and B7–2 (CD86) on human hepatocellular carcinoma. Hepatology 25(5), 1108–1114 (1997).
  • Maki A, Matsuda M, Asakawa M, Kono H, Fujii H, Matsumoto Y. Decreased expression of CD28 coincides with the down-modulation of CD3zeta and augmentation of caspase-3 activity in T cells from hepatocellular carcinoma-bearing patients and hepatitis C virus-infected patients. J. Gastroenterol. Hepatol. 19(12), 1348–1356 (2004).
  • Gonzalez-Carmona MA, Lukacs-Kornek V, Timmerman A et al. CD40ligand-expressing dendritic cells induce regression of hepatocellular carcinoma by activating innate and acquired immunity in vivo. Hepatology 48(1), 157–168 (2008).
  • Iida T, Shiba H, Misawa T, Ohashi T, Eto Y, Yanaga K. Adenovirus-mediated CD40L gene therapy induced both humoral and cellular immunity against rat model of hepatocellular carcinoma. Cancer Sci. 99(10), 2097–2103 (2008).
  • Morales-Kastresana A, Sanmamed MF, Rodriguez I et al. Combined immunostimulatory monoclonal antibodies extend survival in an aggressive transgenic hepatocellular carcinoma mouse model. Clin. Cancer Res. (2013) ( Epub ahead of print).
  • Wan YL, Zheng SS, Zhao ZC, Li MW, Jia CK, Zhang H. Expression of co-stimulator 4–1BB molecule in hepatocellular carcinoma and adjacent non-tumor liver tissue, and its possible role in tumor immunity. World J. Gastroenterol. 10(2), 195–199 (2004).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.