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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

  • Translational Research and Biomarkers
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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

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Acknowledgment

The authors thank Yuki Orito and Amphone Okada for their excellent technical assistance. They also thank the Edanz Group (www.edanzediting.com/ac) 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.

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Authors and Affiliations

  1. Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan

    Tsunehiko Shigemori MD, Yuji Toiyama MD, PhD, FACS, Yoshinaga Okugawa MD, PhD, Akira Yamamoto MD, Chengzeng Yin MD, Aya Narumi MD, Takashi Ichikawa MD, Shozo Ide MD, PhD, Tadanobu Shimura MD, PhD, Hiroyuki Fujikawa MD, PhD, Hiromi Yasuda MD, PhD, Junichiro Hiro MD, PhD, Shigeyuki Yoshiyama MD, PhD, Masaki Ohi MD, PhD, Toshimitsu Araki MD, PhD & Masato Kusunoki MD, PhD

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  1. Tsunehiko Shigemori MD
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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).

Corresponding authors

Correspondence to Yuji Toiyama MD, PhD, FACS or Yoshinaga Okugawa MD, PhD.

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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)

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Shigemori, T., Toiyama, Y., Okugawa, Y. et al. 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. Ann Surg Oncol 26, 876–883 (2019). https://doi.org/10.1245/s10434-018-07112-x

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