Annals of Surgical Oncology

, Volume 26, Issue 3, pp 876–883 | Cite as

Soluble PD-L1 Expression in Circulation as a Predictive Marker for Recurrence and Prognosis in Gastric Cancer: Direct Comparison of the Clinical Burden Between Tissue and Serum PD-L1 Expression

  • Tsunehiko Shigemori
  • Yuji ToiyamaEmail author
  • Yoshinaga OkugawaEmail author
  • Akira Yamamoto
  • Chengzeng Yin
  • Aya Narumi
  • Takashi Ichikawa
  • Shozo Ide
  • Tadanobu Shimura
  • Hiroyuki Fujikawa
  • Hiromi Yasuda
  • Junichiro Hiro
  • Shigeyuki Yoshiyama
  • Masaki Ohi
  • Toshimitsu Araki
  • Masato Kusunoki
Translational Research and Biomarkers



This study assessed programmed cell death ligand 1 (PD-L1) expression in primary tissues and soluble PD-L1 (sPD-L1) concentration in matched preoperative serum in gastric cancer (GC) patients to perform direct comparison between tissue and serum PD-L1 expression and to clarify the prognostic implication in GC.


The study enrolled 180 GC patients who underwent surgery for GC at the authors’ institution. The study evaluated tissue PD-L1 expression using immunohistochemistry and quantified sPD-L1 concentration in preoperative serum using enzyme-linked immunosorbent assay in GC patients.


The findings showed that PD-L1 was overexpressed in GC tissues compared with normal mucosa. Tissue PD-L1 expression was significantly higher in the GC patients with advanced T stage, presence of lympho-vascular invasion, lymph node metastasis, and peritoneal metastasis. Furthermore, elevated tissue PD-L1 expression was significantly associated with poor prognosis for overall survival (OS) and disease-free survival (DFS). Serum sPD-L1 was significantly higher in the GC patients than in the healthy volunteers. Although serum sPD-L1 was not correlated with any clinicopathologic factors, the patients with high serum sPD-L1 showed poorer OS and DFS than those with low sPD-L1. Multivariate analyses showed that both elevated tissue PD-L1 and serum sPD-L1 were independent prognostic factors for poor OS [tissue PD-L1: hazard ratio (HR), 4.28; 95% confidence interval (CI), 1.43–12.8; P = 0.0094 vs. serum sPD-L1: HR, 11.2; 95% CI, 3.44–36.7; P = 0.0001] and poor DFS (tissue PD-L1: HR, 6.96; 95% CI, 2.48–19.6; P = 0.0002 vs. serum sPD-L1: HR, 8.7; 95% CI, 3.16–23.9; P < 0.0001) for the GC patients. Furthermore, infiltrative CD8- and Foxp3-positive T cells were significantly increased in the GC patients with elevated tissue PD-L1 expression.


Both serum sPD-L1 and tissue PD-L1 expression may serve as predictive biomarkers for recurrence and prognosis in GC patients.



The authors thank Yuki Orito and Amphone Okada for their excellent technical assistance. They also thank the Edanz Group ( for editing a draft of this manuscript. A part of this study was supported by a Grant in Aid for Scientific Research (16K10533) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

Author Contributions

Study concept and design (TS, YT, YO, TS, KM); provision of samples (TI, SI, HF, HY, JH, SY, MO, TA, MK); acquisition of data (TS, YO, AY, LY, AN, TS); analysis and interpretation of data (TS, YT, YO, HY, SY, MO); statistical analysis (TS, YT, YO); drafting the manuscript (TS, YT, YO, MK).


There are no conflicts of interest.

Supplementary material

10434_2018_7112_MOESM1_ESM.docx (24 kb)
Supplementary material 1 (DOCX 24 kb)
Fig. S1 Scoring system for immunohistochemical analysis of programmed cell death ligand 1 (PD-L1) expression in gastric cancer (GC). a–d The intensity of PD-L1 staining was scored as (a) 0 (negative) (b) 1 (weak), (c) 2 (moderate), or (d) 3 (strong). e–h The extent of PD-L1 staining was scored as the percentage of cancer cells with cytoplasmic staining: 0 (0%), (e) 1 (1–25%), (f) 2 (25–50%), (g) 3 (51–75%), or (h) 4 (76–100%). Representative images are shown. All images were captured at a magnification of × 200. (TIF 6928 kb)
Fig. S2 Correlation between tissue programmed cell death ligand 1 (PD-L1) and serum soluble PD-L1 (sPD-L1) levels in gastric cancer (GC) patients. The preoperative serum sPD-1 showed a tendency toward elevation in the GC patients with high tissue PD-L1 expression versus those with low tissue PD-L1 expression. A significant correlation was not observed (P = 0.1). (TIF 493 kb)
Fig. S3 Immunohistochemical staining of CD8- and Foxp3- positive tumor-infiltrating lymphocytes (TILs). a CD8-positive TILs density in marginal part (original magnification × 400). b Intratumoral densities of CD8-positive stained cells in the marginal part measured using an automatic image analysis system (original magnification × 400). c Foxp3-positive TILs density in the marginal part (original magnification × 400). d Intratumoral densities of Foxp3-positive stained cells in the marginal part measured using an automatic image analysis system (original magnification × 400). (TIF 4008 kb)


  1. 1.
    Kashihara H, Shimada M, Yoshikawa K, et al. Risk factors for recurrence of gastric cancer after curative laparoscopic gastrectomy. J Med Investig. 2017;64:79–84.CrossRefGoogle Scholar
  2. 2.
    Marano L, Polom K, Patriti A, et al. Surgical management of advanced gastric cancer: an evolving issue. Eur J Surg Oncol. 2016;42:18–27.CrossRefGoogle Scholar
  3. 3.
    Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67:7–30.CrossRefGoogle Scholar
  4. 4.
    Vennin C, Murphy KJ, Morton JP, Cox TR, Pajic M, Timpson P. Reshaping the tumor stroma for treatment of pancreatic cancer. Gastroenterology. 2018;154:820–38.CrossRefGoogle Scholar
  5. 5.
    Bertucci F, Finetti P, Perrot D, et al. PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas. Oncoimmunology. 2017;6:e1278100.CrossRefGoogle Scholar
  6. 6.
    Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70.CrossRefGoogle Scholar
  7. 7.
    Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29:235–71.CrossRefGoogle Scholar
  8. 8.
    Jiang X, Shapiro DJ. The immune system and inflammation in breast cancer. Mol Cell Endocrinol. 2014;382:673–82.CrossRefGoogle Scholar
  9. 9.
    Bertucci F, Finetti P, Mamessier E, et al. PDL1 expression is an independent prognostic factor in localized GIST. Oncoimmunology. 2015;4:e1002729.CrossRefGoogle Scholar
  10. 10.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefGoogle Scholar
  11. 11.
    Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390:1853–62.CrossRefGoogle Scholar
  12. 12.
    Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small cell lung cancer. N Engl J Med. 2015;372:2018–28.CrossRefGoogle Scholar
  13. 13.
    Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:2461–71.CrossRefGoogle Scholar
  14. 14.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.CrossRefGoogle Scholar
  15. 15.
    Afreen S, Dermime S. The immunoinhibitory B7-H1 molecule as a potential target in cancer: killing many birds with one stone. Hematol Oncol Stem Cell Ther. 2014;7:1–17.CrossRefGoogle Scholar
  16. 16.
    Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother. 2005;54:307–14.CrossRefGoogle Scholar
  17. 17.
    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
  18. 18.
    Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13:2151–7.CrossRefGoogle Scholar
  19. 19.
    Kim JW, Nam KH, Ahn SH, et al. Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer. Gastric Cancer. 2016;19:42–52.CrossRefGoogle Scholar
  20. 20.
    Velcheti V, Schalper KA, Carvajal DE, et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest. 2014;94:107–16.CrossRefGoogle Scholar
  21. 21.
    Boland JM, Kwon ED, Harrington SM, et al. Tumor B7-H1 and B7-H3 expression in squamous cell carcinoma of the lung. Clin Lung Cancer. 2013;14:157–63.CrossRefGoogle Scholar
  22. 22.
    Spranger S, Spaapen RM, Zha Y, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Translat Med. 2013;5:200ra116.CrossRefGoogle Scholar
  23. 23.
    Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. Cancer. 2005;104:2084–91.CrossRefGoogle Scholar
  24. 24.
    Chen Y, Wang Q, Shi B, 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
  25. 25.
    Rossille D, Gressier M, Damotte D, et al. 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. 2014;28:2367–75.CrossRefGoogle Scholar
  26. 26.
    Wang L, Wang H, Chen H, et al. Serum levels of soluble programmed death ligand 1 predict treatment response and progression free survival in multiple myeloma. Oncotarget. 2015;6:41228–36.Google Scholar
  27. 27.
    Mori K, Toiyama Y, Saigusa S, et al. Systemic analysis of predictive biomarkers for recurrence in colorectal cancer patients treated with curative surgery. Dig Dis Sci. 2015;60:2477–87.CrossRefGoogle Scholar
  28. 28.
    Ha H, Nam AR, Bang JH, et al. Soluble programmed death-ligand 1 (sPDL1) and neutrophil-to-lymphocyte ratio (NLR) predicts survival in advanced biliary tract cancer patients treated with palliative chemotherapy. Oncotarget. 2016;7:76604–12.Google Scholar
  29. 29.
    Lin G, Fan X, Zhu W, et al. Prognostic significance of PD-L1 expression and tumor infiltrating lymphocyte in surgically resectable non-small cell lung cancer. Oncotarget. 2017;8:83986–94.Google Scholar
  30. 30.
    Ceeraz S, Nowak EC, Noelle RJ. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol. 2013;34:556–63.CrossRefGoogle Scholar
  31. 31.
    Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229:114–25.CrossRefGoogle Scholar
  32. 32.
    Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exper Med. 2009;206:3015–29.CrossRefGoogle Scholar
  33. 33.
    He J, Hu Y, Hu M, Li B. Development of PD-1/PD-L1 pathway in tumor immune microenvironment and treatment for non-small cell lung cancer. Sci Rep. 2015;5:13110.CrossRefGoogle Scholar
  34. 34.
    Frigola X, Inman BA, Lohse CM, et al. Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma. Clin Cancer Res. 2011;17:1915–23.CrossRefGoogle Scholar
  35. 35.
    Tamura T, Ohira M, Tanaka H, et al. Programmed death-1 ligand-1 (pdl1) expression is associated with the prognosis of patients with stage II/III gastric cancer. Anticancer Res. 2015;35:5369–76.Google Scholar
  36. 36.
    Zhang M, Dong Y, Liu H, et al. The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer: a meta-analysis of 10 studies with 1901 patients. Sci Rep. 2016;6:37933.CrossRefGoogle Scholar
  37. 37.
    Brody R, Zhang Y, Ballas M, et al. PD-L1 expression in advanced NSCLC: insights into risk stratification and treatment selection from a systematic literature review. Lung Cancer Amsterdam. 2017;112:200–15.CrossRefGoogle Scholar
  38. 38.
    Wu P, Wu D, Li L, Chai Y, Huang J. PD-L1 and survival in solid tumors: a meta-analysis. PloS One. 2015;10:e0131403.CrossRefGoogle Scholar
  39. 39.
    Ju X, Shen R, Huang P, et al. Predictive relevance of PD-L1 expression with pre-existing TILs in gastric cancer. Oncotarget. 2017;8:99372–81.Google Scholar
  40. 40.
    Amatatsu M, Arigami T, Uenosono Y, et al. PD-L1 is a promising blood marker for predicting tumor progression and prognosis in patients with gastric cancer. Cancer Sci. 2018;109:814–20.CrossRefGoogle Scholar
  41. 41.
    Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting SRC homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA. 2001;98:13866–71.CrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2018

Authors and Affiliations

  • Tsunehiko Shigemori
    • 1
  • Yuji Toiyama
    • 1
    Email author
  • Yoshinaga Okugawa
    • 1
    Email author
  • Akira Yamamoto
    • 1
  • Chengzeng Yin
    • 1
  • Aya Narumi
    • 1
  • Takashi Ichikawa
    • 1
  • Shozo Ide
    • 1
  • Tadanobu Shimura
    • 1
  • Hiroyuki Fujikawa
    • 1
  • Hiromi Yasuda
    • 1
  • Junichiro Hiro
    • 1
  • Shigeyuki Yoshiyama
    • 1
  • Masaki Ohi
    • 1
  • Toshimitsu Araki
    • 1
  • Masato Kusunoki
    • 1
  1. 1.Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of MedicineMie UniversityMieJapan

Personalised recommendations