Annals of Surgical Oncology

, Volume 25, Issue 12, pp 3755–3763 | Cite as

Prognostic Impact of Immune-Related Gene Expression in Preoperative Peripheral Blood from Gastric Cancer Patients

  • Shuhei Ito
  • Takeo Fukagawa
  • Miwa Noda
  • Qingjiang Hu
  • Sho Nambara
  • Dai Shimizu
  • Yosuke Kuroda
  • Hidetoshi Eguchi
  • Takaaki Masuda
  • Tetsuya Sato
  • Hitoshi Katai
  • Mitsuru Sasako
  • Koshi MimoriEmail author
Translational Research and Biomarkers



Anti-PD-1 therapy has shown a promising clinical outcome in gastric cancer (GC). We evaluated the clinical significance of systemic immune-related gene expression in GC patients who underwent surgery.


The correlation between the preoperative PD-1, PD-L1, and CD8 mRNA levels in peripheral blood (PB) and clinicopathological factors, including survival, in 372 GC patients was evaluated using quantitative RT-PCR. PD-1- and PD-L1-expressing cells were identified by flow cytometric analysis.


The PD-1, PD-L1, and CD8 mRNA levels in GC patients were significantly higher than those in normal controls, respectively (all P < 0.0001). The levels of each gene were positively correlated with those of the other two genes (all P < 0.0001). GC patients with low PD-1, high PD-L1, and low CD8 mRNA levels had significantly poorer overall survival (OS) than those with high PD-1, low PD-L1, and high CD8 mRNA levels, respectively (P < 0.01, P < 0.05, and P < 0.05, respectively). Multivariate analysis showed that low PD-1 and high PD-L1 mRNA levels were independent poor prognostic factors for OS (PD-1: HR 2.38, 95% CI 1.27–4.78, P < 0.01; PD-L1: HR 1.81, 95% CI 1.15–2.78, P < 0.05). PD-1 and PD-L1 expression occurred on T cells (> 90%) and T cells or monocytes (> 70%), respectively.


The PD-1, PD-L1, and CD8 mRNA levels in preoperative PB reflected the anti-tumour immune response, and the low PD-1 and high PD-L1 mRNA levels in PB were independent poor prognostic markers in GC patients who underwent surgery.



The authors thank all the patients that provided samples for the study. We thank Ms. Kazumi Oda, Ms. Michiko Kasagi, and Ms. Sachiko Sakuma for their technical assistance; Dr. Reiko Takahashi and Dr. Daisuke Oryoji for their advice for flow cytometric analysis; and members of the Department of Surgery, Kyushu University Beppu Hospital for technical assistance and discussion. This work was supported in part by Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (C) (Grand 17K10593 to S.I.), Daiwa Securities Health Foundation (to S.I.), and Oita Cancer Research Foundation (to S.I.).


The authors declare no conflict of interest.

Supplementary material

10434_2018_6739_MOESM1_ESM.xlsx (32 kb)
Supplementary material 1 (XLSX 32 kb)
10434_2018_6739_MOESM2_ESM.xlsx (39 kb)
Supplementary material 2 (XLSX 39 kb)
10434_2018_6739_MOESM3_ESM.pdf (128 kb)
mRNA expression of PD-1, PD-L1, and CD8 in peripheral blood of GC patients with or without preoperative chemotherapy. The median and fold increases of mRNA expression in patients with preoperative chemotherapy versus those without preoperative chemotherapy are shown. The P values were calculated by the Mann–Whitney U test (PDF 128 kb)
10434_2018_6739_MOESM4_ESM.pdf (46 kb)
Survival rates in patients with GC classified by low and high ratio of PD-L1/PD-1 mRNA levels in peripheral blood. The OS of 372 GC patients who underwent surgery and the DFS of 338 GC patients who underwent curative surgery are shown (PDF 45 kb)


  1. 1.
    Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974–82.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Muro K, Chung HC, Shankaran V, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016;17(6):717–26.CrossRefPubMedGoogle Scholar
  4. 4.
    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(10111):2461–71.CrossRefPubMedGoogle Scholar
  5. 5.
    Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–33.CrossRefPubMedGoogle Scholar
  6. 6.
    Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–50.CrossRefPubMedGoogle Scholar
  7. 7.
    Patel SP, Kurzrock R. PD-L1 Expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14(4):847–56.CrossRefPubMedGoogle Scholar
  8. 8.
    Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Wu P, Wu D, Li L, Chai Y, Huang J. PD-L1 and survival in solid tumors: a meta-analysis. PLoS One. 2015;10(6):e0131403.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016;16(5):275–87.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.CrossRefPubMedGoogle Scholar
  12. 12.
    Mimori K, Fukagawa T, Kosaka Y, et al. Hematogenous metastasis in gastric cancer requires isolated tumor cells and expression of vascular endothelial growth factor receptor-1. Clin Cancer Res. 2008;14(9):2609–16.CrossRefPubMedGoogle Scholar
  13. 13.
    Iwatsuki M, Fukagawa T, Mimori K, et al. Bone marrow and peripheral blood expression of ID1 in human gastric carcinoma patients is a bona fide indicator of lymph node and peritoneal metastasis. Br J Cancer. 2009;100(12):1937–42.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Iwaya T, Fukagawa T, Suzuki Y, et al. Contrasting expression patterns of histone mRNA and microRNA 760 in patients with gastric cancer. Clin Cancer Res. 2013;19(23):6438–49.CrossRefPubMedGoogle Scholar
  15. 15.
    Japanese Gastric Cancer A. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14(2):101–12.CrossRefGoogle Scholar
  16. 16.
    Iinuma H, Okinaga K, Egami H, et al. Usefulness and clinical significance of quantitative real-time RT-PCR to detect isolated tumor cells in the peripheral blood and tumor drainage blood of patients with colorectal cancer. Int J Oncol. 2006;28(2):297–306.PubMedGoogle Scholar
  17. 17.
    Mori M, Mimori K, Inoue H, et al. Detection of cancer micrometastases in lymph nodes by reverse transcriptase-polymerase chain reaction. Cancer Res. 1995;55(15):3417–20.PubMedGoogle Scholar
  18. 18.
    Mizuno H, Kitada K, Nakai K, Sarai A. PrognoScan: a new database for meta-analysis of the prognostic value of genes. BMC Med Genomics. 2009;2:18.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRefPubMedGoogle Scholar
  20. 20.
    Ethun CG, Bilen MA, Jani AB, Maithel SK, Ogan K, Master VA. Frailty and cancer: implications for oncology surgery, medical oncology, and radiation oncology. CA Cancer J Clin. 2017;67(5):362–77.CrossRefPubMedGoogle Scholar
  21. 21.
    Lin JP, Lin JX, Cao LL, et al. Preoperative lymphocyte-to-monocyte ratio as a strong predictor of survival and recurrence for gastric cancer after radical-intent surgery. Oncotarget. 2017;8(45):79234–47.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Lieto E, Galizia G, Auricchio A, et al. Preoperative neutrophil to lymphocyte ratio and lymphocyte to monocyte ratio are prognostic factors in gastric cancers undergoing surgery. J Gastrointest Surg. 2017;21(11):1764–74.CrossRefPubMedGoogle Scholar
  23. 23.
    Ito M, Oshima Y, Yajima S, et al. Is high serum programmed death ligand 1 level a risk factor for poor survival in patients with gastric cancer? Ann Gastroenterol Surg. 2018;2(4):313–8.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kleffel S, Posch C, Barthel SR, et al. Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell. 2015;162(6):1242–56.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Society of Surgical Oncology 2018

Authors and Affiliations

  • Shuhei Ito
    • 1
    • 2
  • Takeo Fukagawa
    • 3
    • 4
  • Miwa Noda
    • 1
  • Qingjiang Hu
    • 1
  • Sho Nambara
    • 1
  • Dai Shimizu
    • 1
  • Yosuke Kuroda
    • 1
  • Hidetoshi Eguchi
    • 1
  • Takaaki Masuda
    • 1
  • Tetsuya Sato
    • 5
  • Hitoshi Katai
    • 3
  • Mitsuru Sasako
    • 3
    • 6
  • Koshi Mimori
    • 1
    Email author
  1. 1.Department of SurgeryKyushu University Beppu HospitalBeppuJapan
  2. 2.Department of SurgeryNational Fukuoka-Higashi Medical CenterKogaJapan
  3. 3.Department of Gastric SurgeryNational Cancer Center HospitalTokyoJapan
  4. 4.Department of SurgeryTeikyo University School of MedicineTokyoJapan
  5. 5.Division of Bioinformatics, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
  6. 6.Department of SurgeryHyogo College of MedicineNishinomiyaJapan

Personalised recommendations