Meta-Analysis

Evaluation of PD-L1 as a biomarker for immunotherapy for hepatocellular carcinoma: systematic review and meta-analysis

School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, China

Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province, 310016, China

‡Contributed equally

Search for more papers by this author

Jiasheng Cao‡

https://orcid.org/0000-0002-4047-8899

Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province, 310016, China

School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China

‡Contributed equally

Search for more papers by this author

Win Topatana

https://orcid.org/0000-0001-8580-1920

School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China

Search for more papers by this author

Tianao Xie

https://orcid.org/0000-0003-1738-4840

Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, 511436, China

Search for more papers by this author

Tianen Chen

https://orcid.org/0000-0002-0412-5447

Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province, 310016, China

School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China

Search for more papers by this author

Jiahao Hu

https://orcid.org/0000-0001-5835-1012

Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province, 310016, China

School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China

Search for more papers by this author

Shijie Li

https://orcid.org/0000-0002-7583-4523

Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province, 310016, China

School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China

Search for more papers by this author

Sarun Juengpanic

https://orcid.org/0000-0002-1449-5564

School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China

Search for more papers by this author

Ziyi Lu

https://orcid.org/0000-0002-8209-3188

School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

Search for more papers by this author

Bin Zhang

https://orcid.org/0000-0002-6888-811X

Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province, 310016, China

School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China

Search for more papers by this author

Kaitai Wang

https://orcid.org/0000-0001-6138-0201

School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, China

Search for more papers by this author

Xu Feng

https://orcid.org/0000-0002-4445-8174

Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province, 310016, China

School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China

Search for more papers by this author

Jiliang Shen

https://orcid.org/0000-0001-9702-4735

Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province, 310016, China

School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China

Search for more papers by this author

Mingyu Chen

*Author for correspondence: Tel: +86 571 8600 6617,

E-mail Address: mychen@zju.edu.cn

https://orcid.org/0000-0001-5113-754X

Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province, 310016, China

School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China

Search for more papers by this author

Published Online:27 Feb 2023https://doi.org/10.2217/imt-2022-0168

View article

Abstract

Aim: To determine if PD-L1 can be used as a biomarker to predict the efficacy of anti-PD-1/PD-L1 inhibitors in hepatocellular carcinoma (HCC). Methods: Relevant studies from a specific search of the four databases from October 2014 to December 2022 were included in this meta-analysis. Results: Higher PD-L1 expression levels were associated with a higher objective response rate (ORR). Higher PD-L1 expression levels on tumor cells and tumor proportion score were associated with higher ORR. PD-L1 was capable of predicting the effectiveness of nivolumab. Dako 28-8 is a promising assay for HCC. Conclusion: PD-L1 is a predictive biomarker for ORR in HCC. Tumor proportion score and PD-L1 expression levels on tumor cells are potential scoring algorithms.

Plain language summary

Clinically, liver cancer patients with high PD-L1 levels may not benefit from immunotherapy. Conversely, some patients with low PD-L1 level can benefit from it. Therefore, the concept of PD-L1 as a predictive indicator in liver cancer is defective. Whether PD-L1 can serve as an indicator in liver cancer patients receiving immunotherapy needs urgent confirmation. In this work, we evaluated the feasibility of PD-L1 as a prognostic biomarker for immunotherapy. The results suggested that high expression of PD-L1 by tumor cells rather than tumor tissue was correlated with better prognosis.

Keywords:

Papers of special note have been highlighted as: •• of considerable interest

References

1. Bray F, Ferlay J, Soerjomataram I et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68(6), 394–424 (2018).
MedlineGoogle Scholar
2. Zhang L, Ding J, Li HY et al. Immunotherapy for advanced hepatocellular carcinoma, where are we? Biochim. Biophys. Acta. Rev. Cancer 1874(2), 188441 (2020).
Medline CASGoogle Scholar
3. Xia S, Pan Y, Liang Y et al. The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma. EBioMedicine 51, 102610 (2020).
MedlineGoogle Scholar
4. Rizzo A, Ricci AD, Gadaleta-Caldarola G, Brandi G. First-line immune checkpoint inhibitor-based combinations in unresectable hepatocellular carcinoma: current management and future challenges. Expert Rev. Gastroenterol. Hepatol. 15(11), 1245–1251 (2021).
Medline CASGoogle Scholar
5. Kole C, Charalampakis N, Tsakatikas S et al. Immunotherapy for hepatocellular carcinoma: a 2021 update. Cancers (Basel) 12(10), 1–28 (2020).
Google Scholar
6. Jiang Y, Han QJ, Zhang J. Hepatocellular carcinoma: mechanisms of progression and immunotherapy. World J. Gastroenterol. 25(25), 3151–3167 (2019).
Medline CASGoogle Scholar
7. Shojaie L, Ali M, Iorga A, Dara L. Mechanisms of immune checkpoint inhibitor-mediated liver injury. Acta Pharm. Sin. B 11(12), 3727–3739 (2021).
Medline CASGoogle Scholar
8. Pinter M, Scheiner B, Peck-Radosavljevic M. Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups. Gut 70(1), 204–214 (2021).
Medline CASGoogle Scholar
9. Lei Q, Wang D, Sun K et al. Resistance mechanisms of anti-PD1/PDL1 therapy in solid tumors. Front. Cell Dev. Biol. 8, 672 (2020).
MedlineGoogle Scholar
10. Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 18(8), 525–543 (2021).
MedlineGoogle Scholar
11. Calderaro J, Rousseau B, Amaddeo G et al. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology 64(6), 2038–2046 (2016).
Medline CASGoogle Scholar
12. Topalian SL, Hodi FS, Brahmer JR et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366(26), 2443–2454 (2012).
Medline CASGoogle Scholar
13. Patsoukis N, Wang Q, Strauss L, Boussiotis VA. Revisiting the PD-1 pathway. Sci. Adv. 6(38), 1–13 (2020).
Google Scholar
14. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol. Cancer Ther. 14(4), 847–856 (2015).
Medline CASGoogle Scholar
15. Rui X, Gu TT, Pan HF, Zhang HZ. Evaluation of PD-L1 biomarker for immune checkpoint inhibitor (PD-1/PD-L1 inhibitors) treatments for urothelial carcinoma patients: a meta-analysis. Int. Immunopharmacol. 67, 378–385 (2019).
Medline CASGoogle Scholar
16. Zhang B, Liu Y, Zhou S et al. Predictive effect of PD-L1 expression for immune checkpoint inhibitor (PD-1/PD-L1 inhibitors) treatment for non-small cell lung cancer: a meta-analysis. Int. Immunopharmacol. 80, 106214 (2020).
Medline CASGoogle Scholar
17. Liberati A, Altman DG, Tetzlaff J et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339, b2700 (2009).
MedlineGoogle Scholar
18. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339, b2535 (2009).
MedlineGoogle Scholar
19. Methley AM, Campbell S, Chew-Graham C et al. PICO, PICOS and SPIDER: a comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews. BMC Health Serv. Res. 14, 579 (2014).
MedlineGoogle Scholar
20. Qin S, Ren Z, Meng Z et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 21(4), 571–580 (2020). •• Provided important original data for our work.
Medline CASGoogle Scholar
21. Mori R, Futamura M, Morimitsu K et al. The mode of progressive disease affects the prognosis of patients with metastatic breast cancer. World J. Surg. Oncol. 16(1), 169 (2018).
MedlineGoogle Scholar
22. Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat. Methods Med. Res. 27(6), 1785–1805 (2018).
MedlineGoogle Scholar
23. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med. Res. Methodol. 14, 135 (2014).
MedlineGoogle Scholar
24. 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. Lancet 389(10088), 2492–2502 (2017). •• Provided important original data for our work.
Medline CASGoogle Scholar
25. Feun LG, Li YY, Wu C et al. Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma. Cancer 125(20), 3603–3614 (2019). •• Provided important original data for our work.
Medline CASGoogle Scholar
26. Lee PC, Chao Y, Chen MH et al. Predictors of response and survival in immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma. Cancers (Basel) 12(1), 1–14 (2020). •• Provided important original data for our work.
Google Scholar
27. Xu J, Shen J, Gu S et al. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): a nonrandomized, open-label, phase II trial. Clin. Cancer Res. 27(4), 1003–1011 (2021). •• Provided important original data for our work.
Medline CASGoogle Scholar
28. Yau T, Hsu C, Kim TY et al. Nivolumab in advanced hepatocellular carcinoma: sorafenib-experienced Asian cohort analysis. J. Hepatol. 71(3), 543–552 (2019). •• Provided important original data for our work.
Medline CASGoogle Scholar
29. Yau T, Park JW, Finn RS et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 23(1), 77–90 (2022). •• Provided important original data for our work.
Medline CASGoogle Scholar
30. Zhu AX, Finn RS, Edeline J 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. 19(7), 940–952 (2018). •• Provided important original data for our work.
MedlineGoogle Scholar
31. Gu X, Gao XS, Xiong W et al. Increased programmed death ligand-1 expression predicts poor prognosis in hepatocellular carcinoma patients. Onco. Targets Ther. 9, 4805–4813 (2016).
Medline CASGoogle Scholar
32. Zong Z, Zou J, Mao R et al. M1 macrophages induce PD-L1 expression in hepatocellular carcinoma cells through IL-1β signaling. Front. Immunol. 10, 1643 (2019).
Medline CASGoogle Scholar
33. Zhang W, Liu Y, Yan Z et al. IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma. J. Immunother. Cancer 8(1), 1–14 (2020).
Google Scholar
34. Doroshow DB, Bhalla S, Beasley MB et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol. 18(6), 345–362 (2021).
Medline CASGoogle Scholar
35. Fu Y, Liu S, Zeng S, Shen H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 38(1), 396 (2019).
MedlineGoogle Scholar
36. Yarchoan M, Xing D, Luan L et al. Characterization of the immune microenvironment in hepatocellular carcinoma. Clin. Cancer Res. 23(23), 7333–7339 (2017).
Medline CASGoogle Scholar
37. Hegde PS, Chen DS. Top 10 Challenges in cancer immunotherapy. Immunity 52(1), 17–35 (2020).
Medline CASGoogle Scholar
38. Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 12(12), 681–700 (2015).
Medline CASGoogle Scholar
39. Armstrong SA, He AR. Immuno-oncology for hepatocellular carcinoma: the present and the future. Clin. Liver Dis. 24(4), 739–753 (2020).
MedlineGoogle Scholar
40. Sanmamed MF, Chen L. A paradigm shift in cancer immunotherapy: from enhancement to normalization. Cell 175(2), 313–326 (2018).
Medline CASGoogle Scholar
41. Reck M, Rodríguez-Abreu D, Robinson AG et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J. Clin. Oncol. 37(7), 537–546 (2019).
Medline CASGoogle Scholar
42. Balar AV, Galsky MD, Rosenberg JE et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389(10064), 67–76 (2017).
Medline CASGoogle Scholar
43. Chung HC, Ros W, Delord JP et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J. Clin. Oncol. 37(17), 1470–1478 (2019).
Medline CASGoogle Scholar
44. Jotte R, Cappuzzo F, Vynnychenko I et al. Atezolizumab in combination with carboplatin and nab-paclitaxel in advanced squamous NSCLC (IMpower131): results from a randomized phase III trial. J. Thorac. Oncol. 15(8), 1351–1360 (2020).
Medline CASGoogle Scholar
45. Yeong J, Lum HYJ, Teo CB et al. Choice of PD-L1 immunohistochemistry assay influences clinical eligibility for gastric cancer immunotherapy. Gastric Cancer 25(4), 741–750 (2022).
Medline CASGoogle Scholar
46. Huang X, Ding Q, Guo H et al. Comparison of three FDA-approved diagnostic immunohistochemistry assays of PD-L1 in triple-negative breast carcinoma. Hum. Pathol. 108, 42–50 (2021).
Medline CASGoogle Scholar
47. Maule JG, Clinton LK, Graf RP et al. Comparison of PD-L1 tumor cell expression with 22C3, 28-8, and SP142 IHC assays across multiple tumor types. J. Immunother. Cancer 10(10), 1–12 (2022).
Google Scholar

Vol. 15, No. 5

Supplemental Materials

Metrics

Downloaded 209 times

History

Received 1 July 2022

Accepted 1 February 2023

Published online 27 February 2023

Published in print April 2023

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/imt-2022-0168

Author contributions

X Zhou and J Cao made substantial contributions to the conception or design of the work. W Topatana, T Xie and T Chen were responsible for acquisition, analysis or interpretation of data for the work. J Hu, S Li, S Juengpanic, Z Lu, B Zhang and K Wang drafted the work or revising it critically for important intellectual content. X Feng and J Shen were responsible for final approval of the version to be published. M Chen was responsible for agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgments

The authors thank Mr Luo for his edification during the growth of the first author.

Financial & competing interests disclosure

This work was supported by the Fundamental Research Funds for the Central Universities (No. 2022QZJH52). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Data sharing

The authors certify that this manuscript reports the secondary analysis of clinical trial data that have been shared with them and that the use of this shared data is in accordance with the terms (if any) agreed upon their receipt. The sources of these data are: NCT01658878, NCT02576509, NCT03463876, NCT02658019, NCT02989922 and NCT02702414.

PDF download