Virchows Archiv

, Volume 462, Issue 1, pp 73–81 | Cite as

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

  • Jin Ye
  • Hui Liu
  • Yanming Hu
  • Peng Li
  • Gehua Zhang
  • Yuan Li
Original Article

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.

Keywords

Prognostic factor Indoleamine 2,3-dioxygenase Regulatory T lymphocytes Squamous cell carcinomas Tumor-infiltrating lymphocytes 

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

Notes

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.

References

  1. 1.
    Mellor AL, Chandler P, Lee GK et al (2002) Indoleamine 2,3-dioxygenase, immunosuppression and pregnancy. J Reprod Immunol 57:143–150PubMedCrossRefGoogle Scholar
  2. 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 17:6985–6991PubMedCrossRefGoogle Scholar
  3. 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 18:2257–2262PubMedCrossRefGoogle Scholar
  4. 4.
    Johnson BA 3rd, Baban B, Mellor AL (2009) Targeting the immunoregulatory indoleamine 2,3 dioxygenase pathway in immunotherapy. Immunotherapy 1:645–661PubMedGoogle Scholar
  5. 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 9:1269–1274PubMedCrossRefGoogle Scholar
  6. 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 7:565–575PubMedCrossRefGoogle Scholar
  7. 7.
    Sørensen RB, Køllgaard T, Andersen RS et al (2011) Spontaneous cytotoxic T-cell reactivity against indoleamine 2,3-dioxygenase-2. Cancer Res 71:2038–2044PubMedCrossRefGoogle Scholar
  8. 8.
    Mellor AL, Keskin DB, Johnson T et al (2002) Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses. J Immunol 168:3771–3776PubMedGoogle Scholar
  9. 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 9:938–952PubMedCrossRefGoogle Scholar
  10. 10.
    Allen CT, Judd NP, Bui JD et al (2012) The clinical implications of antitumor immunity in head and neck cancer. Laryngoscope 122:144–157PubMedCrossRefGoogle Scholar
  11. 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 134:1247–1253PubMedCrossRefGoogle Scholar
  12. 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 13:6993–7002PubMedCrossRefGoogle Scholar
  13. 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 12:1144–1151PubMedCrossRefGoogle Scholar
  14. 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 11:6030–6039PubMedCrossRefGoogle Scholar
  15. 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 99:2185–2192PubMedCrossRefGoogle Scholar
  16. 16.
    Engin AB, Ozkan Y, Fuchs D et al (2010) Increased tryptophan degradation in patients with bronchus carcinoma. Eur J Cancer Care (Engl) 19:803–808CrossRefGoogle Scholar
  17. 17.
    Suzuki Y, Suda T, Furuhashi K et al (2010) Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer. Lung Cancer 67:361–365PubMedCrossRefGoogle Scholar
  18. 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. 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):352–357PubMedCrossRefGoogle Scholar
  20. 20.
    Liu J, Lu G, Tang F et al (2009) Localization of indoleamine 2,3-dioxygenase in human esophageal squamous cell carcinomas. Virchows Arch 455:441–448PubMedCrossRefGoogle Scholar
  21. 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. 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 10:1573–1586PubMedCrossRefGoogle Scholar
  23. 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):203–213PubMedCrossRefGoogle Scholar
  24. 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 30:1797–1803CrossRefGoogle Scholar
  25. 25.
    Ropponen KM, EskelinenMJ LPK et al (1997) Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 182:318–324PubMedCrossRefGoogle Scholar
  26. 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 14:2310–2317PubMedCrossRefGoogle Scholar
  27. 27.
    Rudensky AY (2011) Regulatory T cells and Foxp3. Immunol Rev 241:260–268PubMedCrossRefGoogle Scholar
  28. 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 18:2215–2221PubMedCrossRefGoogle Scholar
  29. 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. 30.
    Munn DH (2011) Indoleamine 2,3-dioxygenase. Tregs and cancer. Curr Med Chem 18:2240–2246PubMedCrossRefGoogle Scholar
  31. 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):874–881PubMedCrossRefGoogle Scholar
  32. 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 181:5396–5404PubMedGoogle Scholar
  33. 33.
    Katz JB, Muller AJ, Prendergast GC (2008) Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev 222:206–221PubMedCrossRefGoogle Scholar
  34. 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 266:1333–1352PubMedCrossRefGoogle Scholar
  35. 35.
    Mendenhall WM, Mancuso AA, Hinerman RW et al (2007) Multidisciplinary management of laryngeal carcinoma. Int J Radiat Oncol Biol Phys 69:S12–S14PubMedCrossRefGoogle Scholar
  36. 36.
    Marioni G, Marchese-Ragona R, Cartei G et al (2006) Current opinion in diagnosis and treatment of laryngeal carcinoma. Cancer Treat Rev 32:504–515PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Jin Ye
    • 1
  • Hui Liu
    • 2
  • Yanming Hu
    • 3
  • Peng Li
    • 1
  • Gehua Zhang
    • 1
  • Yuan Li
    • 1
  1. 1.Department of Otolaryngology, Head and Neck SurgeryThe Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhouChina
  2. 2.Department of Internal Medicine, Division of Pulmonary and Critical CareThe Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhouChina
  3. 3.Department of Otolaryngology, Head and Neck SurgeryAnhui Provincial HospitalHefeiChina

Personalised recommendations