Skip to main content
Log in

Establishing peripheral PD-L1 as a prognostic marker in hepatocellular carcinoma patients: how long will it come true?

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Background

The prognostic role of intratumoral programmed cell death ligand 1 (PD-L1) expression in hepatocellular carcinoma (HCC) has been investigated by several meta-analyses. However, the prognostic value of pretreatment peripheral PD-L1 (PPPD-L1) level in HCC remains undetermined. Thus, this systemic review aimed to establish PPPD-L1 as a new prognostic marker in HCC according to available evidence.

Methods

Case–control studies investigating the prognostic role of PPPD-L1 in HCC were systemically sought in the database of PubMed and Web of Science until March 25th, 2020. Our main concern is survival results, including overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). The combined results were summarized in narrative form according to data extracted from each included study.

Results

Finally, nine studies published from 2011 to 2019, were incorporated into this systemic review. Among these, six studies evaluated the PD-L1 expression by enzyme-linked immunosorbent assay (ELISA) from blood serum, and three studies evaluated the PD-L1 expression by flow cytometric analysis from peripheral blood mononuclear cells (PBMC). According to the extracted evidence, high PPPD-L1 expression, measured in either blood serum or PBMC, is associated with poor OS, poor DFS, and poor PFS. Meanwhile, PPPD-L1 was also correlated with enlarged tumor size and more likely with advanced tumor stage as well as vascular invasion.

Conclusion

High PPPD-L1 level is associated with increased mortality rate and increased recurrence rate in HCC. As a convenient serum marker, PPPD-L1 could be a promising marker of prognosis in HCC patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Availability of data and material

The data used in this systemic review were directly extracted from the nine included studies.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    Google Scholar 

  2. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301–14.

    PubMed  Google Scholar 

  3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30.

    Google Scholar 

  4. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T cell immunity. Nat Rev Immunol. 2004;4(5):336–47.

    CAS  PubMed  Google Scholar 

  5. Hansen AR, Siu LL. PD-L1 testing in cancer: challenges in companion diagnostic development. JAMA Oncol. 2016;2(1):15–6.

    PubMed  Google Scholar 

  6. Fritz JM, Lenardo MJ. Development of immune checkpoint therapy for cancer. J Exp Med. 2019;216(6):1244–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Kythreotou A, Siddique A, Mauri FA, Bower M, Pinato DJ. PD-L1. J Clin Pathol. 2018;71(3):189–94.

    PubMed  Google Scholar 

  8. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7–H1 promotes T cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800.

    CAS  PubMed  Google Scholar 

  9. Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203(4):883–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, et al. PD-1 alters T cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015;6:6692. https://doi.org/10.1038/ncomms7692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Akinleye A, Rasool Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. J Hematol Oncol. 2019;12(1):92. https://doi.org/10.1186/s13045-019-0779-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016;17(12):e542–e551551.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Li JH, Ma WJ, Wang GG, Jiang X, Chen X, Wu L, et al. Clinicopathologic significance and prognostic value of programmed cell death ligand 1 (PD-L1) in patients with hepatocellular carcinoma: a meta-analysis. Front Immunol. 2018;9:2077. https://doi.org/10.3389/fimmu.2018.02077.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu GM, Li XG, Zhang YM. Prognostic role of PD-L1 for HCC patients after potentially curative resection: a meta-analysis. Cancer Cell Int. 2019;19:22. https://doi.org/10.1186/s12935-019-0738-9.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zhang X, Cheng C, Hou J, Qi X, Wang X, Han P, et al. Distinct contribution of PD-L1 suppression by spatial expression of PD-L1 on tumor and non-tumor cells. Cell Mol Immunol. 2019;16(4):392–400.

    PubMed  Google Scholar 

  17. Shindo Y, Hazama S, Tsunedomi R, Suzuki N, Nagano H. Novel biomarkers for personalized cancer immunotherapy. Cancers (Basel). 2019;11(9):1223. https://doi.org/10.3390/cancers11091223.

    Article  CAS  PubMed Central  Google Scholar 

  18. Macek Jilkova Z, Aspord C, Decaens T. Predictive factors for response to PD-1/PD-L1 checkpoint inhibition in the field of hepatocellular carcinoma: current status and challenges. Cancers (Basel). 2019;11(10):1554. https://doi.org/10.3390/cancers11101554.

    Article  CAS  PubMed Central  Google Scholar 

  19. Fusi A, Festino L, Botti G, Masucci G, Melero I, Lorigan P, et al. PD-L1 expression as a potential predictive biomarker. Lancet Oncol. 2015;16(13):1285–7.

    PubMed  Google Scholar 

  20. Festino L, Botti G, Lorigan P, Masucci GV, Hipp JD, Horak CE, et al. Cancer treatment with Anti-PD-1/PD-L1 agents: is PD-L1 expression a biomarker for patient selection? Drugs. 2016;76(9):925–45.

    CAS  PubMed  Google Scholar 

  21. Sica GL, Ramalingam SS. Assays for PD-L1 expression: do all roads lead to Rome? JAMA Oncol. 2017;3(8):1058–9.

    PubMed  Google Scholar 

  22. Anyaegbu CC, Garrett K, Hemmings C, Lee-Pullen TF, McCoy MJ. Immunohistochemical detection of PD-L1 for research studies: which antibody and what protocol? Pathology. 2017;49(4):427–30.

    CAS  PubMed  Google Scholar 

  23. Han X, Gu YK, Li SL, Chen H, Chen MS, Cai QQ, et al. Pre-treatment serum levels of soluble programmed cell death-ligand 1 predict prognosis in patients with hepatitis B-related hepatocellular carcinoma. J Cancer Res Clin Oncol. 2019;145(2):303–12.

    CAS  PubMed  Google Scholar 

  24. Ma X, Qu X, Yang W, Wang H, Wang B, Shen M, et al. Soluble programmed death-ligand 1 indicate poor prognosis in hepatocellular carcinoma patients undergoing transcatheter arterial chemoembolization. Ann Oncol. 2019;30(5):v283–284.

    Google Scholar 

  25. Chang B, Huang T, Wei H, Shen L, Zhu D, He W, et al. The correlation and prognostic value of serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) in patients with hepatocellular carcinoma. Cancer Immunol Immunother. 2019;68(3):353–63.

    CAS  PubMed  Google Scholar 

  26. El-Gebaly F, Abou-Saif S, Elkadeem M, Helmy A, Abd-Elsalam S, Yousef M, et al. Study of serum soluble programmed death ligand 1 as a prognostic factor in hepatocellular carcinoma in Egyptian patients. Curr Cancer Drug Targets. 2019;19(11):896–905.

    CAS  PubMed  Google Scholar 

  27. 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(1):130–5.

    CAS  PubMed  Google Scholar 

  28. 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.

    CAS  PubMed  Google Scholar 

  29. Iwata T, Kondo Y, Kimura O, Morosawa T, Fujisaka Y, Umetsu T, et al. PD-L1+MDSCs are increased in HCC patients and induced by soluble factor in the tumor microenvironment. Sci Rep. 2016;6:39296.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 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. https://doi.org/10.1371/journal.pone.0023621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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(4):887–96.

    CAS  PubMed  Google Scholar 

  32. Ocker M. Biomarkers for hepatocellular carcinoma: what's new on the horizon? World J Gastroenterol. 2018;24(35):3974–9.

    PubMed  PubMed Central  Google Scholar 

  33. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589–604.

    PubMed  PubMed Central  Google Scholar 

  34. Canale M, Ulivi P, Foschi FG, Scarpi E, De Matteis S, Donati G, et al. Clinical and circulating biomarkers of survival and recurrence after radiofrequency ablation in patients with hepatocellular carcinoma. Crit Rev Oncol Hematol. 2018;129:44–53.

    PubMed  Google Scholar 

  35. Shi Y. Regulatory mechanisms of PD-L1 expression in cancer cells. Cancer Immunol Immunother. 2018;67(10):1481–9.

    CAS  PubMed  Google Scholar 

  36. Wu Y, Chen W, Xu ZP, Gu W. PD-L1 distribution and perspective for cancer immunotherapy-blockade, knockdown, or inhibition. Front Immunol. 2019;10:2022. https://doi.org/10.3389/fimmu.2019.02022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–544.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sidaway P. PD-L1 positivity predicts response. Nat Rev Clin Oncol. 2019;16(6):337. https://doi.org/10.1038/s41571-019-0199-z.

    Article  CAS  PubMed  Google Scholar 

  39. Otoshi T, Nagano T, Tachihara M, Nishimura Y. Possible biomarkers for cancer immunotherapy. Cancers (Basel). 2019;11(7):935.

    CAS  Google Scholar 

  40. Kudo M. Scientific rationale for combined immunotherapy with PD-1/PD-L1 antibodies and VEGF inhibitors in advanced hepatocellular carcinoma. Cancers (Basel). 2020;12(5):E1089. https://doi.org/10.3390/cancers12051089.

    Article  CAS  PubMed  Google Scholar 

  41. Feng Z, Rong P, Wang W. Meta-analysis of the efficacy and safety of PD-1/PD-L1 inhibitors administered alone or in combination with anti-VEGF agents in advanced hepatocellular carcinoma. Gut. 2019. https://doi.org/10.1136/gutjnl-2019-320116(Epub 2019 Dec 18).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Carbognin L, Pilotto S, Milella M, Vaccaro V, Brunelli M, Caliò A, et al. Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): sensitivity analysis of trials in melanoma, lung and genitourinary cancers. PLoS ONE. 2015;10(6):e0130142. https://doi.org/10.1371/journal.pone.0130142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shen X, Zhao B. Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ. 2018;362:k3529. https://doi.org/10.1136/bmj.k3529.

    Article  PubMed  PubMed Central  Google Scholar 

  44. 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(8):1920–8.

    CAS  PubMed  Google Scholar 

  45. Lo Russo G, Moro M, Sommariva M, Cancila V, Boeri M, Centonze G, et al. Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade. Clin Cancer Res. 2019;25(3):989–99.

    CAS  PubMed  Google Scholar 

  46. Xie Q, Chen Z, Xia L, Zhao Q, Yu H, Yang Z. Correlations of PD-L1 gene polymorphisms with susceptibility and prognosis in hepatocellular carcinoma in a Chinese Han population. Gene. 2018;674:188–94.

    CAS  PubMed  Google Scholar 

  47. Sideras K, de Man RA, Harrington SM, Polak WG, Zhou G, Schutz HM, et al. Circulating levels of PD-L1 and Galectin-9 are associated with patient survival in surgically treated Hepatocellular Carcinoma independent of their intra-tumoral expression levels. Sci Rep. 2019;9(1):10677.

    PubMed  PubMed Central  Google Scholar 

  48. Wilson JK, Zhao Y, Singer M, Spencer J, Shankar-Hari M. Lymphocyte subset expression and serum concentrations of PD-1/PD-L1 in sepsis—pilot study. Crit Care. 2018;22(1):95.

    PubMed  PubMed Central  Google Scholar 

  49. Liu M, Zhang X, Chen H, Wang G, Zhang J, Dong P, et al. Serum sPD-L1, upregulated in sepsis, may reflect disease severity and clinical outcomes in septic patients. Scand J Immunol. 2017;85(1):66–72.

    CAS  PubMed  Google Scholar 

  50. Zhao Y, Jia Y, Li C, Fang Y, Shao R. The risk stratification and prognostic evaluation of soluble programmed death-1 on patients with sepsis in emergency department. Am J Emerg Med. 2018;36(1):43–8.

    PubMed  Google Scholar 

  51. Yamagiwa S, Ishikawa T, Waguri N, Sugitani S, Kamimura K, Tsuchiya A, et al. Increase of soluble programmed cell death ligand 1 in patients with chronic hepatitis C. Int J Med Sci. 2017;14(5):403–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Kuol N, Stojanovska L, Nurgali K, Apostolopoulos V. PD-1/PD-L1 in disease. Immunotherapy. 2018;10(2):149–60.

    CAS  PubMed  Google Scholar 

  53. Skibinski DA. Noninvasive detection of PD-L1 on circulating tumor cells in patient blood samples. Future Oncol. 2018;14(13):1237–40.

    CAS  PubMed  Google Scholar 

  54. Sidaway P. Deglycosylated PD-L1 might be a better biomarker. Nat Rev Clin Oncol. 2019;16(10):592.

    PubMed  Google Scholar 

  55. 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-alpha and -gamma and mediates T cell apoptosis. J Hepatol. 2006;45(4):520–8.

    PubMed  Google Scholar 

  56. Chen DP, Ning WR, Jiang ZZ, Peng ZP, Zhu LY, Zhuang SM, et al. Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3-PD-L1 axis in human hepatocellular carcinoma. J Hepatol. 2019;71(2):333–43.

    CAS  PubMed  Google Scholar 

  57. Zou J, Zhuang M, Yu X, Li N, Mao R, Wang Z, et al. MYC inhibition increases PD-L1 expression induced by IFN-γ in hepatocellular carcinoma cells. Mol Immunol. 2018;101:203–9.

    CAS  PubMed  Google Scholar 

  58. Itoh S, Yoshizumi T, Yugawa K, Imai D, Yoshiya S, Takeishi K, et al. Impact of immune response on outcomes in hepatocellular carcinoma: association with vascular formation. Hepatology. 2020. https://doi.org/10.1002/hep.31206(Epub 2020 Feb 29).

    Article  PubMed  Google Scholar 

  59. 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(6):2038–46.

    CAS  PubMed  Google Scholar 

Download references

Funding

Not applicable.

Author information

Authors and Affiliations

Authors

Contributions

SDW, SXD, and LGY participated in the conception and design of this review. SDW performed the data analysis. SDW along with AL and HHY wrote this manuscript. All these authors have reviewed and approved the final version of the manuscript.

Corresponding authors

Correspondence to X.-d. Sun or G.-y. Lv.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval (research involving human participants and/or animals)

For this type of study, ethics approval is not required.

Inform consent

For this type of study, formal consent is not required.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, Dw., An, L., Huang, Hy. et al. Establishing peripheral PD-L1 as a prognostic marker in hepatocellular carcinoma patients: how long will it come true?. Clin Transl Oncol 23, 82–91 (2021). https://doi.org/10.1007/s12094-020-02390-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-020-02390-y

Keywords

Navigation