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Annals of Surgical Oncology

, Volume 26, Issue 1, pp 190–199 | Cite as

The Predictive Value of Pretreatment Neutrophil-To-Lymphocyte Ratio in Esophageal Squamous Cell Carcinoma

  • Miao-Fen ChenEmail author
  • Ping-Tsung Chen
  • Feng-Che Kuan
  • Wen-Cheng Chen
Gastrointestinal Oncology

Abstract

Background

The neutrophil-to-lymphocyte ratio (NLR) has been reported to be both a prognostic biomarker for cancer and associated with inflammation, but its predictive role in tumor immunity is not clear. The present study examined the correlations of the NLR and immune suppression with the prognoses in patients with esophageal squamous cell carcinoma (ESCC).

Methods

We performed a retrospective review of 1168 patients who were newly diagnosed with stage T1N(+) and T2–T4 ESCC at our hospital. The NLR of each ESCC patient prior to treatment was calculated, and the associations of the NLR with various clinicopathological parameters and prognoses were then examined. In addition, correlations of the proportion of myeloid-derived suppressor cells (MDSCs) and level of interleukin (IL)-6 with the NLR were assessed in 242 ESCC patients.

Results

An elevated NLR was significantly correlated with advanced-stage disease and reduced overall survival (OS) of ESCC patients. Furthermore, the levels of IL-6 in tumors and MDSCs in the peripheral circulation were significantly correlated with the prognoses of ESCC, and the NLR was positively correlated with MDSC levels in the circulation and IL-6 staining intensity in tumor specimens. Moreover, a high NLR was significantly associated with reduced OS in the 926 patients treated with concomitant chemoradiotherapy, but not in the 242 patients who underwent surgical intervention.

Conclusion

The NLR may represent a clinically useful biomarker to guide ESCC treatment decisions. Patients with a higher NLR may be an optimal subgroup for IL-6- and MDSC-targeted therapy.

Notes

Acknowledgment

The authors would like to thank the Health Information and Epidemiology Laboratory (CLRPG6G0041) for the comments and assistance in data analysis.

Funding

The work was support by the Ministry of Science and Technology, Taiwan (Grant Number 1052628-B-182A-009-MY3, to M.F. Chen).

Compliance with ethical standards

Conflict of interest

Miao-Fen Chen, Ping-Tsung Chen, Feng-Che Kuan, and Wen-Cheng Chen declare that they have no competing interests. All authors read and approved the final version of the manuscript submitted for publication.

Supplementary material

10434_2018_6944_MOESM1_ESM.docx (166 kb)
Supplementary material 1 (DOCX 166 kb)

References

  1. 1.
    Napier KJ, Scheerer M, Misra S. Esophageal cancer: a review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol. 2014;6(5):112–20.CrossRefGoogle Scholar
  2. 2.
    Amenabar A, Hoppo T, Jobe BA. Surgical management of gastroesophageal junction tumors. Semin Radiat Oncol. 2013;23(1):16–23.CrossRefGoogle Scholar
  3. 3.
    Steyerberg EW, Neville BA, Koppert LB et al. Surgical mortality in patients with esophageal cancer: development and validation of a simple risk score. J Clin Oncol. 2006;24(26):4277–84.CrossRefGoogle Scholar
  4. 4.
    Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol. 2009;27(30):5062–7.CrossRefGoogle Scholar
  5. 5.
    Jang R, Darling G, Wong RK. Multimodality approaches for the curative treatment of esophageal cancer. J Natl Compr Canc Netw. 2015;13(2):229–38.CrossRefGoogle Scholar
  6. 6.
    Lee PC, Port JL, Paul S, Stiles BM, Altorki NK. Predictors of long-term survival after resection of esophageal carcinoma with nonregional nodal metastases. Ann Thorac Surg. 2009;88(1):186–92; discussion 192–183.CrossRefGoogle Scholar
  7. 7.
    Chen MF, Chen PT, Lu MS, Lee CP, Chen WC. Survival benefit of surgery to patients with esophageal squamous cell carcinoma. Sci Rep. 2017;7:46139.CrossRefGoogle Scholar
  8. 8.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRefGoogle Scholar
  9. 9.
    McMillan DC. The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer. Cancer Treat Rev. 2013;39(5):534–40.CrossRefGoogle Scholar
  10. 10.
    Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–99.CrossRefGoogle Scholar
  11. 11.
    Houghton AM. The paradox of tumor-associated neutrophils: fueling tumor growth with cytotoxic substances. Cell Cycle. 2010;9(9):1732–37.CrossRefGoogle Scholar
  12. 12.
    Dumitru CA, Moses K, Trellakis S, Lang S, Brandau S. Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology. Cancer Immunol Immunother. 2012;61(8):1155–67.CrossRefGoogle Scholar
  13. 13.
    Guthrie GJ, Charles KA, Roxburgh CS, Horgan PG, McMillan DC, Clarke SJ. The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol. 2013;88(1):218–30.CrossRefGoogle Scholar
  14. 14.
    Yodying H, Matsuda A, Miyashita M, et al. Prognostic significance of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in oncologic outcomes of esophageal cancer: a systematic review and meta-analysis. Ann Surg Oncol. 2016;23(2):646–54.CrossRefGoogle Scholar
  15. 15.
    Takenaka Y, Oya R, Kitamiura T et al. Prognostic role of neutrophil-to-lymphocyte ratio in head and neck cancer: a meta-analysis. Head Neck. 2018;40(3):647–55.CrossRefGoogle Scholar
  16. 16.
    Bunt SK, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S. Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol. 2006;176(1):284–90.CrossRefGoogle Scholar
  17. 17.
    Smyth MJ, Cretney E, Kershaw MH, Hayakawa Y. Cytokines in cancer immunity and immunotherapy. Immunol Rev. 2004;202:275–93.CrossRefGoogle Scholar
  18. 18.
    Chen MF, Chen PT, Lu MS, Lin PY, Chen WC, Lee KD. IL-6 expression predicts treatment response and outcome in squamous cell carcinoma of the esophagus. Mol Cancer. 2013;12:26.CrossRefGoogle Scholar
  19. 19.
    Chen MF, Kuan FC, Yen TC et al. IL-6-stimulated CD11b + CD14 + HLA-DR− myeloid-derived suppressor cells, are associated with progression and poor prognosis in squamous cell carcinoma of the esophagus. Oncotarget. 2014;5(18):8716–28.Google Scholar
  20. 20.
    Ruscetti FW. Hematologic effects of interleukin-1 and interleukin-6. Curr Opin Hematol. 1994;1(3):210–15.Google Scholar
  21. 21.
    Srivastava RM, Lee SC, Andrade Filho PA, et al. Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients. Clin Cancer Res. 2013;19(7):1858–72.CrossRefGoogle Scholar
  22. 22.
    Treffers LW, Hiemstra IH, Kuijpers TW, van den Berg TK, Matlung HL. Neutrophils in cancer. Immunol Rev. 2016;273(1):312–28.CrossRefGoogle Scholar
  23. 23.
    Templeton AJ, McNamara MG, Seruga B, et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst. 2014;106(6):dju124.CrossRefGoogle Scholar
  24. 24.
    Xie X, Luo KJ, Hu Y, Wang JY, Chen J. Prognostic value of preoperative platelet-lymphocyte and neutrophil-lymphocyte ratio in patients undergoing surgery for esophageal squamous cell cancer. Dis Esophagus. 2016;29(1):79–85.CrossRefGoogle Scholar
  25. 25.
    Sharaiha RZ, Halazun KJ, Mirza F et al. Elevated preoperative neutrophil:lymphocyte ratio as a predictor of postoperative disease recurrence in esophageal cancer. Ann Surg Oncol. 2011;18(12):3362–9.CrossRefGoogle Scholar
  26. 26.
    Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–7.CrossRefGoogle Scholar
  27. 27.
    Tran Janco JM, Lamichhane P, Karyampudi L, Knutson KL. Tumor-infiltrating dendritic cells in cancer pathogenesis. J Immunol. 2015;194(7):2985–91.CrossRefGoogle Scholar
  28. 28.
    Kitamura H, Ohno Y, Toyoshima Y, et al. Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy. Cancer Sci. 2017;108(10):1947–52.CrossRefGoogle Scholar
  29. 29.
    Setrerrahmane S, Xu H. Tumor-related interleukins: old validated targets for new anti-cancer drug development. Mol Cancer. 2017;16(1):153.CrossRefGoogle Scholar
  30. 30.
    Yan B, Wei JJ, Yuan Y, et al. IL-6 cooperates with G-CSF to induce protumor function of neutrophils in bone marrow by enhancing STAT3 activation. J Immunol. 2013;190(11):5882–93.CrossRefGoogle Scholar
  31. 31.
    Rose-John S, Waetzig GH, Scheller J, Grotzinger J, Seegert D. The IL-6/sIL-6R complex as a novel target for therapeutic approaches. Expert Opin Ther Targets. 2007;11(5):613–24.CrossRefGoogle Scholar
  32. 32.
    Schupp J, Krebs FK, Zimmer N, Trzeciak E, Schuppan D, Tuettenberg A. Targeting myeloid cells in the tumor sustaining microenvironment. Cell Immunol. Epub 2 Nov 2017.  https://doi.org/10.1016/j.cellimm.2017.10.013.
  33. 33.
    Moses K, Brandau S. Human neutrophils: their role in cancer and relation to myeloid-derived suppressor cells. Semin Immunol. 2016;28(2):187–96.CrossRefGoogle Scholar
  34. 34.
    Bunt SK, Yang L, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res. 2007;67(20):10019–26.CrossRefGoogle Scholar
  35. 35.
    Xu M, Zhao Z, Song J et al. Interactions between interleukin-6 and myeloid-derived suppressor cells drive the chemoresistant phenotype of hepatocellular cancer. Exp Cell Res. 2017;351(2):142–9.CrossRefGoogle Scholar
  36. 36.
    Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017;5(1):3–8.CrossRefGoogle Scholar
  37. 37.
    Bronte V, Brandau S, Chen SH et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150.CrossRefGoogle Scholar
  38. 38.
    Almand B, Clark JI, Nikitina E et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001;166(1):678–89.CrossRefGoogle Scholar
  39. 39.
    Najjar YG, Finke JH. Clinical perspectives on targeting of myeloid derived suppressor cells in the treatment of cancer. Front Oncol. 2013;3:49.CrossRefGoogle Scholar
  40. 40.
    Grutzner E, Stirner R, Arenz L et al. Kinetics of human myeloid-derived suppressor cells after blood draw. J Transl Med. 2016;14:2.CrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2018

Authors and Affiliations

  • Miao-Fen Chen
    • 1
    • 2
    Email author
  • Ping-Tsung Chen
    • 2
    • 3
  • Feng-Che Kuan
    • 2
    • 3
  • Wen-Cheng Chen
    • 1
    • 2
  1. 1.Department of Radiation OncologyChang Gung Memorial HospitalChiayiTaiwan
  2. 2.College of MedicineChang Gung UniversityTaoyuanTaiwan
  3. 3.Department of Hematology and OncologyChang Gung Memorial HospitalChiayiTaiwan

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