Abstract
Purpose
Anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) therapy has shown promise in tumor immunotherapy. Our objectives were to measure pre-treatment serum-soluble PD-L1 (sPD-L1) levels and to assess the relationships between sPD-L1 levels and clinical characteristics, prognosis, and tumor tissue PD-L1 expression in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).
Methods
Pre-treatment serum sPD-L1 levels were measured with an enzyme-linked immunosorbent assay (ELISA) in 81 patients with HBV-related HCC and compared to those in 49 healthy controls. The association between serum sPD-L1 levels and prognosis was assessed using survival analysis. The correlation between paired serum sPD-L1 levels and tumor PD-L1 expression (in resected tissue homogenates) was assessed in a separate group of 20 patients with HBV-related HCC.
Results
Median sPD-L1 concentration in patients with HBV-related HCC was 5.129 (range 0.140–12.391) ng/mL and in healthy controls was 0.836 (range 0.105–2.168) ng/mL (p < 0.001). On multivariate analysis, sPD-L1 levels were significant independent predictors of disease-free survival (hazard ratio [HR] 3.503; 95% confidence interval [CI], 1.559–7.871; p = 0.002) and overall survival (HR 3.399; 95% CI 1.308–8.831; p = 0.012). Positive correlation (r = 0.527, p = 0.017) between serum sPD-L1 and tumor PD-L1 expression was observed. Tumor expression of PD-L1 was significantly higher in those with serum sPD-L1 concentrations above vs. below the median level of 5.471 ng/ml (p = 0.012).
Conclusions
In patients with HBV-related HCC, serum sPD-L1 concentrations were elevated, and positively correlated with tumor PD-L1 expression. Lower pre-treatment serum sPD-L1 levels were predictors of more favorable disease-free and overall survival. Serum sPD-L1 testing has a potential role in HBV-related HCC disease assessment, systemic therapy choices and survival prediction.
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Abbreviations
- HCC:
-
Hepatocellular carcinoma
- PD-1:
-
Programmed cell death-1
- PD-L1:
-
Programmed cell death-ligand 1
- sPD-L1:
-
Soluble PD-L1
- HBV:
-
Hepatitis B virus
- OS:
-
Overall survival
- DFS:
-
Disease-free survival
- mRECIST:
-
Modified response evaluation criteria in solid tumors
- ELISA:
-
Enzyme-linked immunosorbent assay
- EASL:
-
European Association for the Study of the Liver
- CEA:
-
Carcinoembryonic antigen
- AFP:
-
Alpha-fetoprotein
- TNM:
-
Tumor, node, metastases
- BCLC:
-
Barcelona Clinic Liver Cancer
- CLIP:
-
Cancer of the Liver Italian Program
References
Calderaro J, Rousseau B, Amaddeo G, Mercey M, Charpy C, Costentin C, Luciani A, Zafrani ES, Laurent A, Azoulay D, Lafdil F, Pawlotsky JM (2016) Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology 64(6):2038–2046
Chen Y, Wang Q, Shi B, Xu P, Hu Z, Bai L, Zhang X (2011) 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 56(2):231–238
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela CC, Lang L, Neely J, Tang H, Dastani HB, Melero I (2017) 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
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386
Finkelmeier F, Canli Ö, Tal A, Pleli T, Trojan J, Schmidt M, Kronenberger B, Zeuzem S, Piiper A, Greten FR, Waidmann O (2016) High levels of the soluble programmed death-ligand (sPD-L1) identify hepatocellular carcinoma patients with a poor prognosis. Eur J Cancer 59(12):152–159
Frigola X, Inman BA, Krco CJ, Liu X, Harrington SM, Bulur PA, Dietz AB, Dong H, Kwon ED (2012) Soluble B7-H1: differences in production between dendritic cells and T cells. Immunol Lett 142(1–2):78–82
Galle PR, Forner A, Llovet JM, Mazzaferro V, Piscaglia F, Raoul JL, Schirmacher P, Vilgrain V (2018) EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 69(1):182–236
Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, Zhou J, Li BZ, Shi YH, **ao YS, Xu Y, Fan J (2009) Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 15(3):971–979
Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y (2010) Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 116(7):1757–1766
Jung HI, Jeong D, Ji S, Ahn TS, Bae SH, Chin S, Chung JC, Kim HC, Lee MS, Baek MJ (2017) Overexpression of PD-L1 and PD-L2 Is Associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res Treat 49(1):246–254
Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M (2004) B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res 10(15):5094–5100
Kudo M (2017) Immune checkpoint inhibition in hepatocellular carcinoma: basics and ongoing clinical trials. Oncology 92(Suppl 1(1):50–62
Nara S, Shimada K, Sakamoto Y, Esaki M, Kishi Y, Kosuge T, Ojima H (2012) Prognostic impact of marginal resection for patients with solitary hepatocellular carcinoma: evidence from 570 hepatectomies. Surgery 151(4):526–536
Rossille D, Gressier M, Damotte D, Maucort-Boulch D, Pangault C, Semana G, Le GS, Haioun C, Tarte K, Lamy T, Milpied N, Fest T (2014) High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell lymphoma: results from a French multicenter clinical trial. Leukemia 28(12):2367–2375
Shi SJ, Wang LJ, Wang GD, Guo ZY, Wei M, Meng YL, Yang AG, Wen WH (2013) B7-H1 expression is associated with poor prognosis in colorectal carcinoma and regulates the proliferation and invasion of HCT116 colorectal cancer cells. PLoS One 8(10):e76012
Simon I, Zhuo S, Corral L, Diamandis EP, Sarno MJ, Wolfert RL, Kim NW (2006) B7-h4 is a novel membrane-bound protein and a candidate serum and tissue biomarker for ovarian cancer. Cancer Res 66(3):1570–1575
Takahashi N, Iwasa S, Sasaki Y, Shoji H, Honma Y, Takashima A, Okita NT, Kato K, Hamaguchi T, Yamada Y (2016) Serum levels of soluble programmed cell death ligand 1 as a prognostic factor on the first-line treatment of metastatic or recurrent gastric cancer. J Cancer Res Clin Oncol 142(8):1727–1738
Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27(4):450–461
Umemoto Y, Okano S, Matsumoto Y, Nakagawara H, Matono R, Yoshiya S, Yamashita Y, Yoshizumi T, Ikegami T, Soejima Y, Harada M, Aishima S, Oda Y, Shirabe K, Maehara Y (2015) Prognostic impact of programmed cell death 1 ligand 1 expression in human leukocyte antigen class I-positive hepatocellular carcinoma after curative hepatectomy. J Gastroenterol 50(1):65–75
Wang L, Wang H, Chen H, Wang WD, Chen XQ, Geng QR, **a ZJ, Lu Y (2015) Serum levels of soluble programmed death ligand 1 predict treatment response and progression free survival in multiple myeloma. Oncotarget 6(38):41228–41236
Wang H, Wang L, Liu WJ, **a ZJ, Huang HQ, Jiang WQ, Li ZM, Lu Y (2016) High post-treatment serum levels of soluble programmed cell death ligand 1 predict early relapse and poor prognosis in extranodal NK/T cell lymphoma patients. Oncotarget 7(22):33035–33045
**e QK, Zhao YJ, Pan T, Lyu N, Mu LW, Li SL, Shi MD, Zhang ZF, Zhou PH, Zhao M (2016) Programmed death ligand 1 as an indicator of pre-existing adaptive immune responses in human hepatocellular carcinoma. Oncoimmunology 5(7):e1181252
Yamagiwa S, Ishikawa T, Waguri N, Sugitani S, Kamimura K, Tsuchiya A, Takamura M, Kawai H, Terai S (2017) Increase of soluble programmed cell death ligand 1 in patients with chronic hepatitis C. Int J Med Sci 14(5):403–411
Yang CY, Lin MW, Chang YL, Wu CT, Yang PC (2014) Programmed cell death-ligand 1 expression in surgically resected stage I pulmonary adenocarcinoma and its correlation with driver mutations and clinical outcomes. Eur J Cancer 50(7):1361–1369
Zhou J, Sun HC, Wang Z, Cong WM, Wang JH, Zeng MS, Yang JM, Bie P, Liu LX, Wen TF (2018) Guidelines for diagnosis and treatment of primary liver cancer in China (2017 Edition). Liver Cancer 7(7):235–260
Funding
The design of the study was supported by the National Natural Science Foundation of China under Grant [no. 81771955]; the Guangzhou Science and Technology Program (key projects of collaborative innovation of health medicine) under Grant [no. 201704020228]; and the Guangzhou Science and Technology Program (key projects of collaborative innovation of production, learning and research) under Grant [no. 201704020134]; Sun Yat-sen University Clinical Trial 5010 Project under Grant [no. 2016002].
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JH, QC, and YG contributed to the conception and design of the study. XH, MZ and JH drafted and reviewed the manuscript. XH, SL, HC and HD participated in data collection and performed the experiments. Min-shan Chen provided the patients’ specimen. YG and XH contributed to the data analysis and interpretation. All authors have read and approved the final manuscript.
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The authors declare that they have no conflict of interest.
Ethical approval
The study was approved by the Institutional Review Committee of Sun Yat-sen University Cancer Centre in Guangzhou, China (YB2015-018-01). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Written informed consent for procedures was obtained from patients and families. All procedures were performed after obtaining informed consent in accordance with the approved protocol.
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Han, X., Gu, Yk., Li, Sl. 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 145, 303–312 (2019). https://doi.org/10.1007/s00432-018-2758-6
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DOI: https://doi.org/10.1007/s00432-018-2758-6