Skip to main content
SpringerLink
Log in

Tumoral indoleamine 2,3-dioxygenase expression predicts poor outcome in laryngeal squamous cell carcinoma

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

The development of laryngeal squamous cell carcinomas (LSCC) is strongly influenced by the host immune system. Indoleamine 2,3-dioxygenase (IDO) can promote and maintain an immunosuppressive microenvironment which can impede the efficacy of anticancer responses. The purpose of the current study is to investigate the prognostic value of intratumoral IDO expression in LSCC. The expression of IDO protein was retrospectively assessed by immunohistochemistry in 187 LSCC patients. The potential association of tumor IDO expression with clinical parameters and tumor-infiltrating lymphocytes (TILs) was analyzed separately. Survival curves were estimated by the Kaplan–Meier method, and differences between groups were determined by log-rank test. Multivariate logistic regression analysis was performed to determine the independent factors associated with survival. Based on the evaluation score, 90 carcinomas (48.1 %) were identified with high IDO expression and 97 carcinomas (51.9 %) showed low expression. Tumor IDO expression was not associated with clinical stage, presence of metastases, and other clinicopathological parameters. Also, high IDO expression was not correlated with tumor-infiltrating CD3+ and CD8+ TILs. Instead it was positively related with the density of FOXP3+ Tregs. Furthermore, multivariate analysis identified a significant association of overall survival and disease-free survival with tumor IDO status. IDO high expression represents a significant negative prognostic factor in patients with LSCC. Current results provide further support for using IDO as an immunotherapeutic target in LSCC. The precise role of tumoral IDO in human LSCC remains to be elucidated in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

DFS:

Disease-free survival

ESCC:

Esophageal squamous cell carcinoma

FOXP3:

Forkhead box P3

HPF:

High power field

HNSCC:

Head and neck squamous cell carcinomas

IHC:

Immunohistochemistry

LSCC:

Laryngeal squamous cell carcinomas

OS:

Overall survival

OSCC:

Oral squamous cell carcinomas

PL:

Partial laryngectomy

RC:

Radiochemotherapy

TIL:

Tumor-infiltrating lymphocytes

TL:

Total laryngectomy

Treg:

Regulatory T lymphocytes

References

  1. Mellor AL, Chandler P, Lee GK et al (2002) Indoleamine 2,3-dioxygenase, immunosuppression and pregnancy. J Reprod Immunol 57:143–150

    Article  PubMed  CAS  Google Scholar 

  2. Godin-Ethier J, Hanafi LA, Piccirillo CA et al (2011) Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res 17:6985–6991

    Article  PubMed  CAS  Google Scholar 

  3. Prendergast GC, Chang MY, Mandik-Nayak L et al (2011) Indoleamine 2,3-dioxygenase as a modifier of pathogenic inflammation in cancer and other inflammation-associated diseases. Curr Med Chem 18:2257–2262

    Article  PubMed  CAS  Google Scholar 

  4. Johnson BA 3rd, Baban B, Mellor AL (2009) Targeting the immunoregulatory indoleamine 2,3 dioxygenase pathway in immunotherapy. Immunotherapy 1:645–661

    PubMed  CAS  Google Scholar 

  5. Uyttenhove C, Pilotte L, Théate I et al (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9:1269–1274

    Article  PubMed  CAS  Google Scholar 

  6. Funeshima N, Fujino M, Kitazawa Y et al (2005) Inhibition of allogeneic T-cell responses by dendritic cells expressing transduced indoleamine 2,3-dioxygenase. J Gene Med 7:565–575

    Article  PubMed  CAS  Google Scholar 

  7. Sørensen RB, Køllgaard T, Andersen RS et al (2011) Spontaneous cytotoxic T-cell reactivity against indoleamine 2,3-dioxygenase-2. Cancer Res 71:2038–2044

    Article  PubMed  Google Scholar 

  8. Mellor AL, Keskin DB, Johnson T et al (2002) Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses. J Immunol 168:3771–3776

    PubMed  CAS  Google Scholar 

  9. Liu X, Newton RC, Friedman SM et al (2009) Indoleamine 2,3-dioxygenase, an emerging target for anti-cancer therapy. Curr Cancer Drug Targets 9:938–952

    Article  PubMed  CAS  Google Scholar 

  10. Allen CT, Judd NP, Bui JD et al (2012) The clinical implications of antitumor immunity in head and neck cancer. Laryngoscope 122:144–157

    Article  PubMed  Google Scholar 

  11. Pan K, Wang H, Chen MS et al (2008) Expression and prognosis role of indoleamine 2,3-dioxygenase in hepatocellular carcinoma. J Cancer Res Clin Oncol 134:1247–1253

    Article  PubMed  CAS  Google Scholar 

  12. Riesenberg R, Weiler C, Spring O et al (2007) Expression of indoleamine 2,3-dioxygenase in tumor endothelial cells correlates with long-term survival of patients with renal cell carcinoma. Clin Cancer Res 13:6993–7002

    Article  PubMed  CAS  Google Scholar 

  13. Brandacher G, Perathoner A, Ladurner R et al (2006) Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res 12:1144–1151

    Article  PubMed  CAS  Google Scholar 

  14. Okamoto A, Nikaido T, Ochiai K et al (2005) Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin Cancer Res 11:6030–6039

    Article  PubMed  CAS  Google Scholar 

  15. Liu H, Zhang T, Li X et al (2008) Predictive value of MMP-7 expression for response to chemotherapy and survival in patients with non-small cell lung cancer. Cancer Sci 99:2185–2192

    Article  PubMed  CAS  Google Scholar 

  16. Engin AB, Ozkan Y, Fuchs D et al (2010) Increased tryptophan degradation in patients with bronchus carcinoma. Eur J Cancer Care (Engl) 19:803–808

    Article  CAS  Google Scholar 

  17. Suzuki Y, Suda T, Furuhashi K et al (2010) Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer. Lung Cancer 67:361–365

    Article  PubMed  Google Scholar 

  18. Yu J, Sun J, Wang SE et al (2011) Upregulated expression of indoleamine 2,3-dioxygenase in primary breast cancer correlates with increase of infiltrated regulatory T cells in situ and lymph node metastasis. Clin Dev Immunol. doi:10.1155/2011/469135

  19. Laimer K, Troester B, Kloss F et al (2011) Expression and prognostic impact of indoleamine 2,3-dioxygenase in oral squamous cell carcinomas. Oral Oncol 47(5):352–357

    Article  PubMed  CAS  Google Scholar 

  20. Liu J, Lu G, Tang F et al (2009) Localization of indoleamine 2,3-dioxygenase in human esophageal squamous cell carcinomas. Virchows Arch 455:441–448

    Article  PubMed  CAS  Google Scholar 

  21. Zhang G, Liu WL, Zhang L et al (2011) Involvement of indoleamine 2,3-dioxygenase in impairing tumor-infiltrating CD8 T-cell functions in esophageal squamous cell carcinoma. Clin Dev Immunol. doi:10.1155/2011/384726

  22. Elkord E, Alcantar-Orozco EM, Dovedi SJ et al (2010) T regulatory cells in cancer: recent advances and therapeutic potential. Expert Opin Biol Ther 10:1573–1586

    Article  PubMed  CAS  Google Scholar 

  23. Zhang L, Conejo-Garcia JR, Katsaros D et al (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348(3):203–213

    Article  PubMed  CAS  Google Scholar 

  24. Vesalainen S, Lipponen P, Talja M et al (1994) Histological grade, perineural infiltration, tumourinfiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinoma. Eur J Cancer 30:1797–1803

    Article  Google Scholar 

  25. Ropponen KM, EskelinenMJ LPK et al (1997) Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 182:318–324

    Article  PubMed  CAS  Google Scholar 

  26. Ino K, Yamamoto E, Shibata K et al (2008) Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin Cancer Res 14:2310–2317

    Article  PubMed  CAS  Google Scholar 

  27. Rudensky AY (2011) Regulatory T cells and Foxp3. Immunol Rev 241:260–268

    Article  PubMed  CAS  Google Scholar 

  28. Fallarino F, Grohmann U (2011) Using an ancient tool for igniting and propagating immune tolerance: IDO as an inducer and amplifier of regulatory T cell functions. Curr Med Chem 18:2215–2221

    Article  PubMed  CAS  Google Scholar 

  29. Sun J, Yu J, Li H et al (2011) Upregulated expression of indoleamine 2,3-dioxygenase in CHO cells induces apoptosis of competent T cells and increases proportion of Treg cells. J Exp Clin Cancer Res. doi:10.1186/1756-9966-30-82

  30. Munn DH (2011) Indoleamine 2,3-dioxygenase. Tregs and cancer. Curr Med Chem 18:2240–2246

    Article  PubMed  CAS  Google Scholar 

  31. Nakamura T, Shima T, Saeki A et al (2007) Expression of indoleamine 2,3-dioxygenase and the recruitment of Foxp3-expressing regulatory T cells in the development and progression of uterine cervical cancer. Cancer Sci 98(6):874–881

    Article  PubMed  CAS  Google Scholar 

  32. Chen W, Liang X, Peterson AJ et al (2008) The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol 181:5396–5404

    PubMed  CAS  Google Scholar 

  33. Katz JB, Muller AJ, Prendergast GC (2008) Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev 222:206–221

    Article  PubMed  CAS  Google Scholar 

  34. Silver CE, Beitler JJ, Shaha AR et al (2009) Current trends in initial management of laryngeal cancer: the declining use of open surgery. Eur Arch Otorhinolaryngol 266:1333–1352

    Article  PubMed  Google Scholar 

  35. Mendenhall WM, Mancuso AA, Hinerman RW et al (2007) Multidisciplinary management of laryngeal carcinoma. Int J Radiat Oncol Biol Phys 69:S12–S14

    Article  PubMed  Google Scholar 

  36. Marioni G, Marchese-Ragona R, Cartei G et al (2006) Current opinion in diagnosis and treatment of laryngeal carcinoma. Cancer Treat Rev 32:504–515

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We gratefully thank Dr. Jinghui Hou and his colleagues (Department of Pathology, Cancer Center, Sun Yat-Sen University) for technical assistance in pathological evaluations.

Conflict of interest

All other authors indicated no potential conflict of interest.

Author information

Authors and Affiliations

  1. Department of Otolaryngology, Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Street, Guangzhou, Guangdong, 510630, China

    Jin Ye, Peng Li, Gehua Zhang & Yuan Li

  2. Department of Internal Medicine, Division of Pulmonary and Critical Care, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Street, Guangzhou, Guangdong, 510630, China

    Hui Liu

  3. Department of Otolaryngology, Head and Neck Surgery, Anhui Provincial Hospital, No. 17, Lujiang Street, Hefei, Anhui, 230001, China

    Yanming Hu

Authors
  1. Jin Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanming Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gehua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jin Ye.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ye, J., Liu, H., Hu, Y. et al. Tumoral indoleamine 2,3-dioxygenase expression predicts poor outcome in laryngeal squamous cell carcinoma. Virchows Arch 462, 73–81 (2013). https://doi.org/10.1007/s00428-012-1340-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-012-1340-x

Keywords

Search

Navigation