Clinical and Translational Oncology

, Volume 21, Issue 6, pp 702–712 | Cite as

Programmed cell death protein-1 (PD-1)/programmed death-ligand-1 (PD-L1) axis in hepatocellular carcinoma: prognostic and therapeutic perspectives

  • T. MocanEmail author
  • Z. Sparchez
  • R. Craciun
  • C. N. Bora
  • D. C. Leucuta
Review Article
Part of the following topical collections:
  1. The Immune System and Cancer\Immunotherapy


Hepatocellular carcinoma (HCC) is the most common primary neoplasia of the liver. There have been tremendous efforts in the development of therapeutic strategies in the last decades. As opposed to other cancer entities immunotherapy has just recently gained popularity in HCC. Among various immunotherapy approaches, programmed cell death protein-1 (PD-1), and its ligand programmed death receptor ligand-1 (PD-L1) axis became one of the most promising pathway of the decade. The scientific interest in PD-1/PD-L1 axis is definitely justified due to: ability to detect PD-L1 expression in patients that underwent resection for HCC with prognostic values; the role of serum PD-L1 as a tool to identify early recurrences and to monitor treatment outcome; PD-1/PDL1 is a highly targetable pathway, with possible predictive markers, and with high clinical applicability that might help us in selecting a subgroup of HCC patients who are most likely to benefit from PD-1/PD-L1 inhibitors. In this review we will first discuss the prognostic role of PD-1/PD-L1 as a bio-marker in various clinical scenarios. Afterwards we will critically analyse the recently published trials with PD-1/PD-L1 inhibitors in HCC either alone or in combination with other treatment modalities. The higher focus will be on clinical rather than preclinical studies. Nevertheless, the strengths and limits of PD-1/PD-L1 axis in both prognosis and therapy of HCC will be highlighted.


Hepatocellular carcinoma Immunotherapy Checkpoint inhibitors Programmed cell death protein-1 Ligand programmed death-ligand-1 


Author contributions

Tudor Mocan and Zeno Sparchez have equally contributed to this paper with conception and design of the study, literature review, drafting critical revision and editing; Rares Craciun was involved in literature review and drafted Fig. 1; Cristina Nelida Bora performed literature review and drafted the initial version; Daniel Corneliu Leucuta supervised the study and revised the manuscript for important intellectual content; all authors have read and approved the final version to be published.


No financial support.

Compliance with ethical standards

Conflict of interest

No potential conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study informed consent is not required.


  1. 1.
    GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385: 117–71.Google Scholar
  2. 2.
    Ferlay J, Soerjomataram II, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:359–86.CrossRefGoogle Scholar
  3. 3.
    European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.CrossRefGoogle Scholar
  4. 4.
    Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009;15:971–9.CrossRefGoogle Scholar
  5. 5.
    Zhong JH, Du XK, Xiang BD, Li LQ. Adjuvant sorafenib in hepatocellular carcinoma: a cautionary comment of STORM trial. World J Hepatol. 2016;8:957–60.CrossRefGoogle Scholar
  6. 6.
    Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27:450–61.CrossRefGoogle Scholar
  7. 7.
    Hato T, Goyal L, Greten TF, Duda DG, Zhu AX. Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology. 2014;60:1776–82.CrossRefGoogle Scholar
  8. 8.
    Chen Z, Shen S, Peng B, Tao J. Intratumoural GM-CSF microspheres and CTLA-4 blockade enhance the antitumour immunity induced by thermal ablation in a subcutaneous murine hepatoma model. Int J Hyperth. 2009;25:374–82.CrossRefGoogle Scholar
  9. 9.
    Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol. 2010;10:753–66.CrossRefGoogle Scholar
  10. 10.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.CrossRefGoogle Scholar
  11. 11.
    El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, 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;389:2492–502.CrossRefGoogle Scholar
  12. 12.
    Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8:328.CrossRefGoogle Scholar
  13. 13.
    Chen RX, Song HY, Dong YY, Hu C, Zheng QD, Xue TC, et al. Dynamic expression patterns of differential proteins during early invasion of hepatocellular carcinoma. PLoS One. 2014;9:e88543.CrossRefGoogle Scholar
  14. 14.
    Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.CrossRefGoogle Scholar
  15. 15.
    Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229:114–25.CrossRefGoogle Scholar
  16. 16.
    Mühlbauer M, Fleck M, Schütz C, Weiss T, Froh M, Blank C, et al. PD-L1 is induced in hepatocytes by viral infection and by interferon-α and -γ and mediates T cell apoptosis. J Hepatol. 2006;45:520–8.CrossRefGoogle Scholar
  17. 17.
    Yu MC, Chen CH, Liang X, Wang L, Gandhi CR, Fung JJ, et al. Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice. Hepatology. 2004;40:1312–21.CrossRefGoogle Scholar
  18. 18.
    Diehl L, Schurich A, Grochtmann R, Hegenbarth S, Chen L, Knolle PA, et al. Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8 + T cell tolerance. Hepatology. 2008;47:296–305.CrossRefGoogle Scholar
  19. 19.
    Kassel R, Cruise MW, Iezzoni JC, Taylor NA, Pruett TL, Hahn YS, et al. Chronically inflamed livers up-regulate expression of inhibitory B7 family members. Hepatology. 2009;50:1625–37.CrossRefGoogle Scholar
  20. 20.
    Kudo M. Immune checkpoint inhibition in hepatocellular carcinoma: basics and ongoing clinical trials. Oncology. 2017;92:50–62.CrossRefGoogle Scholar
  21. 21.
    Shi F, Shi M, Zeng Z, Qi RZ, Liu ZW, Zhang JY, et al. PD-1 and PD-L1 upregulation promotes CD8 + T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer. 2011;128:887–96.CrossRefGoogle Scholar
  22. 22.
    Kan G, Dong W. The expression of PD-L1 APE1 and P53 in hepatocellular carcinoma and its relationship to clinical pathology. Eur Rev Med Pharmacol Sci. 2015;19:3063–71.Google Scholar
  23. 23.
    Calderaro J, Rousseau B, Amaddeo G, Mercey M, Charpy C, Costentin C, et al. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology. 2016;64:2038–46.CrossRefGoogle Scholar
  24. 24.
    Gu X, Gao XS, Xiong W, Guo W, Han L, Bai Y, et al. Increased programmed death ligand-1 expression predicts poor prognosis in hepatocellular carcinoma patients. Onco Targets Ther. 2016;9:4805–13.CrossRefGoogle Scholar
  25. 25.
    Jung HI, Jeong D, Ji S, Ahn TS, Bae SH, Chin S, et al. Overexpression of PD-L1 and PD-L2 is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res Treat. 2017;49:246–54.CrossRefGoogle Scholar
  26. 26.
    Semaan A, Dietrich D, Bergheim D, Dietrich J, Kalff JC, Branchi V, et al. CXCL12 expression and PD-L1 expression serve as prognostic biomarkers in HCC and are induced by hypoxia. Virchows Arch. 2017;470:185–96.CrossRefGoogle Scholar
  27. 27.
    Hu K, Wang ZM, Li JN, Zhang S, Xiao ZF, Tao YM. CLEC1B expression and PD-L1 expression predict clinical outcome in hepatocellular carcinoma with tumor hemorrhage. Transl Oncol. 2018;11:552–8.CrossRefGoogle Scholar
  28. 28.
    Umemoto Y, Okano S, Matsumoto Y, Nakagawara H, Matono R, Yoshiya S, et al. Prognostic impact of programmed cell death 1 ligand 1 expression in human leukocyte antigen class I-positive hepatocellular carcinoma after curative hepatectomy. J Gastroenterol. 2015;50:65–75.CrossRefGoogle Scholar
  29. 29.
    Gabrielson A, Wu Y, Wang H, Jiang J, Kallakury B, Gatalica Z, et al. Intratumoral CD3 and CD8 T-cell densities associated with relapse-free survival in HCC. Cancer Immunol Res. 2016;4:419–30.CrossRefGoogle Scholar
  30. 30.
    Wu K, Kryczek I, Chen L, Zou W, Welling TH. Kupffer cell suppression of CD8 + T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res. 2009;69:8067–75.CrossRefGoogle Scholar
  31. 31.
    Borie F, Bouvier A-M, Herrero A, Faivre J, Launoy G, Delafosse P, et al. Treatment and prognosis of hepatocellular carcinoma: a population based study in France. J Surg Oncol. 2008;98:505–9.CrossRefGoogle Scholar
  32. 32.
    Sparchez Z, Mocan T. Contemporary role of liver biopsy in hepatocellular carcinoma. World J Hepatol. 2018;10:452–61.CrossRefGoogle Scholar
  33. 33.
    Chen Y, Wang Q, Shi B, Xu P, Hu Z, Bai L, et al. Development of a sandwich ELISA for evaluating soluble PD-L1 (CD274) in human sera of different ages as well as supernatants of PD-L1 + cell lines. Cytokine. 2011;56:231–8.CrossRefGoogle Scholar
  34. 34.
    Zeng Z, Shi F, Zhou L, Zhang MN, Chen Y, Chang XJ, 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):e23621.CrossRefGoogle Scholar
  35. 35.
    Kim HJ, Park S, Kim KJ, Seong J. Clinical significance of soluble programmed cell death ligand-1 (sPD-L1) in hepatocellular carcinoma patients treated with radiotherapy. Radiother Oncol. 2018;129:130–5.CrossRefGoogle Scholar
  36. 36.
    Finkelmeier F, Canli Ö, Tal A, Pleli T, Trojan J, Schmidt M, et al. High levels of the soluble programmed death-ligand (sPD-L1) identify hepatocellular carcinoma patients with a poor prognosis. Eur J Cancer. 2016;59:152–9.CrossRefGoogle Scholar
  37. 37.
    Chang B, Shen L, Wang K, Jin J, Huang T, Chen Q, et al. High number of PD-1 positive intratumoural lymphocytes predicts survival benefit of cytokine-induced killer cells for hepatocellular carcinoma patients. Liver Int. 2018;38:1449–58.CrossRefGoogle Scholar
  38. 38.
    Chen CL, Pan QZ, Zhao JJ, Wang Y, Li YQ, Wang QJ, et al. PD-L1 expression as a predictive biomarker for cytokine-induced killer cell immunotherapy in patients with hepatocellular carcinoma. Oncoimmunology. 2016;5(7):e1176653.CrossRefGoogle Scholar
  39. 39.
    Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940–52.CrossRefGoogle Scholar
  40. 40.
    Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2016;2:16018.CrossRefGoogle Scholar
  41. 41.
    Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, 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;389:56–66.CrossRefGoogle Scholar
  42. 42.
    Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54–63.CrossRefGoogle Scholar
  43. 43.
    Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–73.CrossRefGoogle Scholar
  44. 44.
    Greten TF, Sangro B. Targets for immunotherapy of liver cancer. J Hepatol. 2017 (pii: S0168-8278(17)32287-0).Google Scholar
  45. 45.
    Greten TF, Wang XW, Korangy F. Current concepts of immune based treatments for patients with HCC: from basic science to novel treatment approaches. Gut. 2015;64:842–8.CrossRefGoogle Scholar
  46. 46.
    Raufi A, Tirona MT. Prospect of the use of checkpoint inhibitors in hepatocellular cancer treatments. Cancer Manag Res. 2017;9:19–27.CrossRefGoogle Scholar
  47. 47.
    Feng D, Hui X, Shi-Chun L, Yan-Hua B, Li C, Xiao-Hui L, et al. Initial experience of anti-PD1 therapy with nivolumab in advanced hepatocellular carcinoma. Oncotarget. 2017;8:96649–55.Google Scholar
  48. 48.
    Wainberg ZA, Segal NH, Jaeger D, Lee HK, Marshall J, Antonia SJ, et al. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC). J Clin Oncol. 2017;35 (Suppl):4071 Abstr.Google Scholar
  49. 49.
    Kambhampati S, Bauer K, Hwang J, Bocobo AG, Gordon JD, Kelley RK. Nivolumab in advanced hepatocellular carcinoma (HCC) and Child Pugh B (CPB) cirrhosis: safety and clinical outcomes in a retrospective case series. J Clin Oncol. 2018;36(Suppl):496 Abstr.Google Scholar
  50. 50.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J-F, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.CrossRefGoogle Scholar
  51. 51.
    Brown ZJ, Heinrich B, Steinberg SM, Yu SJ, Greten TF. Safety in treatment of hepatocellular carcinoma with immune checkpoint inhibitors as compared to melanoma and non-small cell lung cancer. J Immunother Cancer. 2017;5:93.CrossRefGoogle Scholar
  52. 52.
    Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016;17:542–51.CrossRefGoogle Scholar
  53. 53.
    San-Chi C. Fever after anti-programmed cell death-1 treatment to predict the response in advanced hepatocellular carcinoma. J Clin Oncol. 2018;36:90.Google Scholar
  54. 54.
    Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res. 2017;23:1920–8.CrossRefGoogle Scholar
  55. 55.
    Chowdhury PS, Chamoto K, Honjo T. Combination therapy strategies for improving PD-1 blockade efficacy: a new era in cancer immunotherapy. J Intern Med. 2018;283:110–20.CrossRefGoogle Scholar
  56. 56.
    Wang Y, Li H, Liang Q, Liu B, Mei X, Ma Y. Combinatorial immunotherapy of sorafenib and blockade of programmed death-ligand 1 induces effective natural killer cell responses against hepatocellular carcinoma. Tumor Biol. 2014;36:1561–6.CrossRefGoogle Scholar
  57. 57.
    Chen SC, Chao Y, Yang MH. Complete response to the combination of pembrolizumab and sorafenib for metastatic hepatocellular carcinoma: a case report. Am J Gastroenterol. 2017;112:659–60.CrossRefGoogle Scholar
  58. 58.
    Makarova-Rusher OV, Medina-Echeverz J, Duffy AG, Greten TF. The yin and yang of evasion and immune activation in HCC. J Hepatol. 2015;62:1420–9.CrossRefGoogle Scholar
  59. 59.
    Kelley RK, Abou-Alfa GK, Bendell JC, Kim TY, Borad MJ, Yong WP, et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase I safety and efficacy analyses. J Clin Oncol. 2017;35 (Suppl):4073 Abstr.Google Scholar
  60. 60.
    Ayaru L, Pereira SP, Alisa A, Pathan AA, Williams R, Davidson B, et al. Unmasking of alpha-fetoprotein-specific CD4(+) T cell responses in hepatocellular carcinoma patients undergoing embolization. J Immunol. 2007;178:1914–22.CrossRefGoogle Scholar
  61. 61.
    Nobuoka D, Motomura Y, Shirakawa H, Yoshikawa T, Kuronuma T, Takahashi M, et al. Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes. Int J Oncol. 2012;40:63–70.Google Scholar
  62. 62.
    Duffy AG, Ulahannan SV, Makorova-Rusher O, Rahma O, Wedemeyer H, Pratt D, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2017;66:545–51.CrossRefGoogle Scholar
  63. 63.
    Ikeda M, Sung MW, Kudo M, Kobayashi M, Baron AD, Finn RS, et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2018;36 (Suppl):4076 Abstr.Google Scholar
  64. 64.
    Gu P, Park J, Zhong J, Guo S, Hickey R, Aaltonen E, et al. Initial experience of combination nivolumab and local-regional treatment in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2018;36 (Suppl):16149 Abstr.Google Scholar
  65. 65.
    Harding JJ. Immune checkpoint blockade in advanced hepatocellular carcinoma: an update and critical review of ongoing clinical trials. Futur Oncol. 2018;14:2293–302.CrossRefGoogle Scholar
  66. 66.
    Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14:847–56.CrossRefGoogle Scholar
  67. 67.
    Iñarrairaegui M, Melero I, Sangro B. Immunotherapy of hepatocellular carcinoma: facts and hopes. Clin Cancer Res. 2018;24:1518–24.CrossRefGoogle Scholar
  68. 68.
    Contratto M, Wu J. Targeted therapy or immunotherapy? Optimal treatment in hepatocellular carcinoma. World J Gastrointest Oncol. 2018;10:108–14.CrossRefGoogle Scholar
  69. 69.
    Hu K, Wang ZM, Li JN, Zhang S, Xiao ZF, Tao YM. CLEC1B expression and PD-L1 expression predict clinical outcome in hepatocellular carcinoma with tumor hemorrhage. Transl Oncol. 2018;11:552–8.CrossRefGoogle Scholar
  70. 70.
    Friend BD, Venick RS, McDiarmid SV, Zhou X, Naini B, Wang H, et al. Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma. Pediatr Blood Cancer. 2017;64:e26682.CrossRefGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2018

Authors and Affiliations

  1. 1.3rd Medical Department“Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-NapocaCluj-NapocaRomania
  2. 2.Institute for Gastroenterology and HepatologyCluj-NapocaRomania
  3. 3.Medical Informatics and Biostatistics Department“Iuliu Hatieganu” University of Medicine and PharmacyCluj-NapocaRomania

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