Hepatology International

, Volume 13, Issue 5, pp 521–533 | Cite as

Clinical immunology and immunotherapy for hepatocellular carcinoma: current progress and challenges

  • Lifeng Wang
  • Fu-Sheng WangEmail author
Review Article


At the time of hepatocellular carcinoma (HCC) diagnosis, patients are most often at an advanced stage; however, the current treatment regimens remain unsatisfactory. Thus, novel and more powerful therapeutic approaches for advanced HCC are urgently required. Exacerbation of immunotolerant signals and/or escaping immunosurveillance leads to the development of HCC, which appears to be a rational reason to use immunotherapy to restore anticancer immunity. Several novel immunotherapeutic methods, including the use of immune checkpoint inhibitors, new types of immune cell adoption [e.g., chimeric antigen receptor T cell (CAR-T), TCR gene-modified T cells and stem cells], and microRNAs have been used in clinical trials for the treatment of HCC. However, some crucial issues remain to be addressed for such novel immunotherapy techniques. Finally, immunotherapy is now standing on the threshold of great advances in the fight against HCC.


Hepatocellular carcinoma Immunological pathogenesis Cancer immune subsets Immunotherapy Immune checkpoint inhibitor 



This work was supported by the National Natural Science Foundation of China, Grant No. 81470837; Innovative Research Groups of the National Natural Science Foundation of China, Grant No. 81721002; Beijing Municipal & Technology Commission Grant No. Z171100001017183. All authors have no financial relationships relevant to this article to disclose.

Compliance with ethical standards

Conflict of interest

Lifeng Wang and Fu-Sheng Wang have no conflicts of interest to disclose.


  1. 1.
    Wallace MC, Preen D, Jeffrey GP, Adams LA. The evolving epidemiology of hepatocellular carcinoma: a global perspective. Expert Rev Gastroenterol Hepatol 2015;9(6):765–779CrossRefGoogle Scholar
  2. 2.
    Wang FS, Fan JG, Zhang Z, Gao B, Wang HY. The global burden of liver disease: the major impact of China. Hepatology 2014;60(6):2099–2108CrossRefGoogle Scholar
  3. 3.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63(1):11–30CrossRefGoogle Scholar
  4. 4.
    Song P, Cai Y, Tang H, Li C, Huang J. The clinical management of hepatocellular carcinoma worldwide: a concise review and comparison of current guidelines from 2001 to 2017. Biosci Trends 2017;11(4):389–398CrossRefGoogle Scholar
  5. 5.
    Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378–390CrossRefGoogle Scholar
  6. 6.
    Kudo M, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018;391(10126):1163–1173CrossRefGoogle Scholar
  7. 7.
    Bruix J, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389(10064):56–66CrossRefGoogle Scholar
  8. 8.
    Allaire M, Nault JC. Advances in management of hepatocellular carcinoma. Curr Opin Oncol 2017;29(4):288–295CrossRefGoogle Scholar
  9. 9.
    Kubes P, Jenne C. Immune responses in the liver. Annu Rev Immunol 2018;26(36):247–277CrossRefGoogle Scholar
  10. 10.
    Ringelhan M, Pfister D, O’Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol 2018;19(3):222–232CrossRefGoogle Scholar
  11. 11.
    Nishida N, Kudo M. Immunological microenvironment of hepatocellular carcinoma and its clinical implication. Oncology 2017;92(Suppl 1):40–49CrossRefGoogle Scholar
  12. 12.
    Ilan Y. Immune therapy for hepatocellular carcinoma. Hepatol Int 2014;8(Suppl 2):499–504CrossRefGoogle Scholar
  13. 13.
    Gelu-Simeon M, Samuel D. Role of cytokine levels in assessment of prognosis and post-treatment outcome in hepatocellular carcinoma. Hepatol Int 2013;7(3):788–791CrossRefGoogle Scholar
  14. 14.
    Malfettone A, et al. Transforming growth factor-beta-induced plasticity causes a migratory stemness phenotype in hepatocellular carcinoma. Cancer Lett 2017;392:39–50CrossRefGoogle Scholar
  15. 15.
    Mi F, Gong L. Secretion of interleukin-6 by bone marrow mesenchymal stem cells promotes metastasis in hepatocellular carcinoma. Biosci Rep 2017. Google Scholar
  16. 16.
    Saalim M, et al. IL-22: a promising candidate to inhibit viral-induced liver disease progression and hepatocellular carcinoma. Tumour Biol 2016;37(1):105–114CrossRefGoogle Scholar
  17. 17.
    Easom NJW, et al. IL-15 overcomes hepatocellular carcinoma-induced NK cell dysfunction. Front Immunol 2018;9:1009CrossRefGoogle Scholar
  18. 18.
    Liu H, et al. Roles of chemokine receptor 4 (CXCR18) and chemokine ligand 12 (CXCL12) in metastasis of hepatocellular carcinoma cells. Cell Mol Immunol 2008;5(5):373–378CrossRefGoogle Scholar
  19. 19.
    Qin LF, et al. CXCL12 and CXCR19 polymorphisms and expressions in peripheral blood from patients of hepatocellular carcinoma. Future Oncol 2018;14(13):1261–1271CrossRefGoogle Scholar
  20. 20.
    Liang CM, et al. Chemokines and their receptors play important roles in the development of hepatocellular carcinoma. World J Hepatol 2015;7(10):1390–1402CrossRefGoogle Scholar
  21. 21.
    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(11):3887–3895CrossRefGoogle Scholar
  22. 22.
    Gao Q, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 2009;15(3):971–979CrossRefGoogle Scholar
  23. 23.
    Shi F, et al. PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer 2011;128(4):887–896CrossRefGoogle Scholar
  24. 24.
    Long J, et al. Expression of programmed death ligand-1 and programmed death 1 in hepatocellular carcinoma and its clinical significance. J Cancer Res Ther 2018;14(Supplement):S1188–S1192Google Scholar
  25. 25.
    Zeng Z, et al. Upregulation of circulating PD-L1/PD-1 is associated with poor post-cryoablation prognosis in patients with HBV-related hepatocellular carcinoma. PLoS One 2011;6(9):e23621CrossRefGoogle Scholar
  26. 26.
    Jung HI, et al. Overexpression of PD-L1 and PD-L2 is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res Treat 2017;49(1):246–254CrossRefGoogle Scholar
  27. 27.
    Gu X, et al. +49G > A polymorphism in the cytotoxic T-lymphocyte antigen-4 gene increases susceptibility to hepatitis B-related hepatocellular carcinoma in a male Chinese population. Hum Immunol 2010;71(1):83–87CrossRefGoogle Scholar
  28. 28.
    Chen X, Du Y, Hu Q, Huang Z. Tumor-derived CD4+ CD25+ regulatory T cells inhibit dendritic cells function by CTLA-4. Pathol Res Pract 2017;213(3):245–249CrossRefGoogle Scholar
  29. 29.
    Inada Y, et al. Characteristics of immune response to tumor-associated antigens and immune cell profile in hepatocellular carcinoma patients. Hepatology 2019;69(2):653–665CrossRefGoogle Scholar
  30. 30.
    Monney L, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002;415(6871):536–541CrossRefGoogle Scholar
  31. 31.
    Li H, 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 2012;56(4):1342–1351CrossRefGoogle Scholar
  32. 32.
    Yan W, et al. Tim-3 fosters HCC development by enhancing TGF-beta-mediated alternative activation of macrophages. Gut 2015;64(10):1593–1604CrossRefGoogle Scholar
  33. 33.
    Li F, et al. Highly elevated soluble Tim-3 levels correlate with increased hepatocellular carcinoma risk and poor survival of hepatocellular carcinoma patients in chronic hepatitis B virus infection. Cancer Manag Res 2018;10:941–951CrossRefGoogle Scholar
  34. 34.
    Khan FS, Ali I, Afridi UK, Ishtiaq M, Mehmood R. Epigenetic mechanisms regulating the development of hepatocellular carcinoma and their promise for therapeutics. Hepatol Int 2017;11(1):45–53CrossRefGoogle Scholar
  35. 35.
    Xie H, et al. microRNA-889 is downregulated by histone deacetylase inhibitors and confers resistance to natural killer cytotoxicity in hepatocellular carcinoma cells. Cytotechnology 2018;70(2):513–521CrossRefGoogle Scholar
  36. 36.
    Xu D, Han Q, Hou Z, Zhang C, Zhang J. miR-146a negatively regulates NK cell functions via STAT1 signaling. Cell Mol Immunol 2017;14(8):712–720CrossRefGoogle Scholar
  37. 37.
    Bian X, et al. Down-expression of miR-152 lead to impaired anti-tumor effect of NK via upregulation of HLA-G. Tumour Biol 2016;37(3):3749–3756CrossRefGoogle Scholar
  38. 38.
    Abdelrahman MM, et al. Enhancing NK cell cytotoxicity by miR-182 in hepatocellular carcinoma. Hum Immunol 2016;77(8):667–673CrossRefGoogle Scholar
  39. 39.
    Zhou SL, et al. miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis. Hepatology 2016;63(5):1560–1575.CrossRefGoogle Scholar
  40. 40.
    Li L, et al. MiR-98 modulates macrophage polarization and suppresses the effects of tumor-associated macrophages on promoting invasion and epithelial–mesenchymal transition of hepatocellular carcinoma. Cancer Cell Int 2018;18:95. CrossRefGoogle Scholar
  41. 41.
    Chen L, et al. Special role of Foxp3 for the specifically altered microRNAs in regulatory T cells of HCC patients. BMC Cancer 2014;14:489. CrossRefGoogle Scholar
  42. 42.
    Wang H, et al. Reciprocal control of miR-197 and IL-6/STAT3 pathway reveals miR-197 as potential therapeutic target for hepatocellular carcinoma. Oncoimmunology 2015;4(10):e1031440CrossRefGoogle Scholar
  43. 43.
    Liu X, Zhang A, Xiang J, Lv Y, Zhang X. miR-451 acts as a suppressor of angiogenesis in hepatocellular carcinoma by targeting the IL-6R-STAT3 pathway. Oncol Rep 2016;36(3):1385–1392CrossRefGoogle Scholar
  44. 44.
    Sandbothe M, et al. The microRNA-449 family inhibits TGF-beta-mediated liver cancer cell migration by targeting SOX4. J Hepatol 2017;66(5):1012–1021CrossRefGoogle Scholar
  45. 45.
    Zhang T, et al. Downregulation of miR-542-3p promotes cancer metastasis through activating TGF-beta/Smad signaling in hepatocellular carcinoma. Onco Targets Ther 2018;11:1929–1939CrossRefGoogle Scholar
  46. 46.
    Thorsson V, et al. The immune landscape of cancer. Immunity 2018;48(4):812–830CrossRefGoogle Scholar
  47. 47.
    Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2015;12(12):681–700CrossRefGoogle Scholar
  48. 48.
    Sangro B, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013;59(1):81–88CrossRefGoogle Scholar
  49. 49.
    Duffy AG, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol 2017;66(3):545–551CrossRefGoogle Scholar
  50. 50.
    El-Khoueiry AB, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017;389(10088):2492–2502CrossRefGoogle Scholar
  51. 51.
    Truong P, Rahal A, Kallail KJ. Metastatic hepatocellular carcinoma responsive to pembrolizumab. Cureus 2016;8(6):e631Google Scholar
  52. 52.
    Wehrenberg-Klee E, Goyal L, Dugan M, Zhu AX, Ganguli S. Y-90 Radioembolization combined with a PD-1 inhibitor for advanced hepatocellular carcinoma. Cardiovasc Interv Radiol 2018;41(11):1799–1802CrossRefGoogle Scholar
  53. 53.
    Brahmer JR, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455–2465CrossRefGoogle Scholar
  54. 54.
    Liu CQ, et al. Expression patterns of programmed death ligand 1 correlate with different microenvironments and patient prognosis in hepatocellular carcinoma. Br J Cancer 2018;119(1):80–88CrossRefGoogle Scholar
  55. 55.
    Xu F, Jin T, Zhu Y, Dai C. Immune checkpoint therapy in liver cancer. J Exp Clin Cancer Res 2018;37(1):110CrossRefGoogle Scholar
  56. 56.
    Takayama T, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000;356(9232):802–807CrossRefGoogle Scholar
  57. 57.
    Shi M, et al. Autologous cytokine-induced killer cell therapy in clinical trial phase I is safe in patients with primary hepatocellular carcinoma. World J Gastroenterol 2004;10(8):1146–1151CrossRefGoogle Scholar
  58. 58.
    European Association for the Study of the Liver. Electronic address IEEE, European Association for the Study of the L. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2018;69(1):182–236CrossRefGoogle Scholar
  59. 59.
    Flecken T, et al. Immunodominance and functional alterations of tumor-associated antigen-specific CD8 + T-cell responses in hepatocellular carcinoma. Hepatology 2014;59(4):1415–1126CrossRefGoogle Scholar
  60. 60.
    Zhou G, et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas. Gastroenterology 2017;153(4):1107–1119CrossRefGoogle Scholar
  61. 61.
    Desrichard A, Snyder A, Chan TA. Cancer neoantigens and applications for immunotherapy. Clin Cancer Res 2016;22(4):807–812CrossRefGoogle Scholar
  62. 62.
    Gao H, et al. Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. Clin Cancer Res 2014;20(24):6418–6428CrossRefGoogle Scholar
  63. 63.
    Chen C, et al. Development of T cells carrying two complementary chimeric antigen receptors against glypican-3 and asialoglycoprotein receptor 1 for the treatment of hepatocellular carcinoma. Cancer Immunol Immunother 2017;66(4):475–489CrossRefGoogle Scholar
  64. 64.
    Wang Y, et al. CD133-directed CAR T cells for advanced metastasis malignancies: a phase I trial. Oncoimmunology 2018;7(7):e1440169CrossRefGoogle Scholar
  65. 65.
    Chen Y, et al. Chimeric antigen receptor-engineered T-cell therapy for liver cancer. Hepatobiliary Pancreat Dis Int 2018;17(4):301–309CrossRefGoogle Scholar
  66. 66.
    Qasim W, et al. Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient. J Hepatol 2015;62(2):486–491CrossRefGoogle Scholar
  67. 67.
    Spear TT, et al. TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors. Cancer Immunol Immunother 2016;65(3):293–304CrossRefGoogle Scholar
  68. 68.
    Zhu W, et al. Identification of alpha-fetoprotein-specific T-cell receptors for hepatocellular carcinoma immunotherapy. Hepatology 2018;68(2):574–589CrossRefGoogle Scholar
  69. 69.
    Ning N, et al. Cancer stem cell vaccination confers significant antitumor immunity. Cancer Res 2012;72(7):1853–1864CrossRefGoogle Scholar
  70. 70.
    Wang X, et al. Phase I trial of active specific immunotherapy with autologous dendritic cells pulsed with autologous irradiated tumor stem cells in hepatitis B-positive patients with hepatocellular carcinoma. J Surg Oncol 2015;111(7):862–867CrossRefGoogle Scholar
  71. 71.
    Wang H, Wang J, Shi X, Ding Y. Genetically engineered bone marrow-derived mesenchymal stem cells co-expressing IFN-gamma and IL-10 inhibit hepatocellular carcinoma by modulating MAPK pathway. J BUON 2017;22(6):1517–1524Google Scholar
  72. 72.
    Szoor A, et al. T cell-activating mesenchymal stem cells as a biotherapeutic for HCC. Mol Ther Oncolytics 2017;6:69–79CrossRefGoogle Scholar
  73. 73.
    Fu J, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 2007;132(7):2328–2339CrossRefGoogle Scholar
  74. 74.
    Greten TF, 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 2010;33(2):211–218CrossRefGoogle Scholar
  75. 75.
    Beg MS, et al. Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Investig New Drugs 2017;35(2):180–188CrossRefGoogle Scholar
  76. 76.
    Zhuang L, et al. Activity of IL-12/15/18 primed natural killer cells against hepatocellular carcinoma. Hepatol Int 2019;13(1):75–83CrossRefGoogle Scholar
  77. 77.
    Sun F, Wang JZ, Luo JJ, Wang YQ, Pan Q. Exosomes in the oncobiology, diagnosis, and therapy of hepatic carcinoma: a new player of an old game. Biomed Res Int 2018;2018:2747461Google Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2019

Authors and Affiliations

  1. 1.Treatment and Research Center for Infectious DiseasesThe Fifth Medical Center of PLA General HospitalBeijingChina

Personalised recommendations