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FOXP3+ Cell Density in Primary Tumor Has No Prognostic Impact in Patients with Cutaneous Malignant Melanoma

  • Published:
Pathology & Oncology Research

Abstract

Regulatory T cells (Tregs) have been implicated as inhibitors of antitumor immune reactions. However, data on the relevance of their prevalence at tumor sites in influencing disease outcome are controversial. The aim of our study was to investigate the role in tumor progression and the prognostic impact of the density of lymphocytes expressing FOXP3, a transcription factor expressed predominantly by CD4+CD25+ Tregs, in primary cutaneous melanoma. We examined the infiltration of FOXP3+ cells by immunohistochemistry in tumor samples from 97 patients and evaluated in relation to patient and tumor parameters. The degree of infiltration by FOXP3+ cells did not show correlation with the thickness of melanomas. Moreover, no associations were found with metastasis formation during the 5-year follow-up period, patient survival, or any other clinicopathologic parameters studied. These results suggest that the presence of FOXP3+ lymphocytes in primary tumors is not of prognostic importance in human cutaneous melanoma.

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References

  1. Paschen A, Eichmüller S, Schadendorf D (2004) Identification of tumor antigens and T-cell epitopes, and its clinical application. Cancer Immunol Immunother 53:196–203

    Article  CAS  PubMed  Google Scholar 

  2. Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181–273

    Article  CAS  PubMed  Google Scholar 

  3. Zou W (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5:263–274

    Article  CAS  PubMed  Google Scholar 

  4. Knutson KL, Disis ML, Salazar LG (2007) CD4 regulatory T cells in human cancer pathogenesis. Cancer Immunol Immunother 56:271–285

    Article  PubMed  Google Scholar 

  5. Curiel TJ, Coukos G, Zou L et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949

    Article  CAS  PubMed  Google Scholar 

  6. Hiraoka N, Onozato K, Kosuge T, Hirohashi S (2006) Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12:5423–5434

    Article  CAS  PubMed  Google Scholar 

  7. Bates GJ, Fox SB, Han C et al (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24:5373–5380

    Article  PubMed  Google Scholar 

  8. Kobayashi N, Hiraoka N, Yamagami W et al (2007) FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res 13:902–911

    Article  CAS  PubMed  Google Scholar 

  9. Gao Q, Qiu S-J, Fan J et al (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593

    Article  PubMed  Google Scholar 

  10. Fox SB, Launchbury R, Bates GJ et al (2007) The number of regulatory T cells in prostate cancer is associated with the androgen receptor and hypoxia-inducible factor (HIF)-2α but not HIF-1α. Prostate 67:623–629

    Article  PubMed  Google Scholar 

  11. Siddiqui SA, Frigola X, Bonne-Annee S et al (2007) Tumor-infiltrating Foxp3−CD4+CD25+ T cells predict poor survival in renal cell carcinoma. Clin Cancer Res 13:2075–2081

    Article  CAS  PubMed  Google Scholar 

  12. Badoual C, Hans S, Rodriguez J et al (2006) Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancer. Clin Cancer Res 12:465–472

    Article  CAS  PubMed  Google Scholar 

  13. Salama P, Phillips M, Grieu F et al (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192

    Article  PubMed  Google Scholar 

  14. Álvaro T, Lejeune M, Salvadó MT et al (2005) Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 11:1467–1473

    Article  PubMed  Google Scholar 

  15. Carreras J, Lopez-Guillermo A, Fox BC et al (2006) High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood 108:2957–2964

    Article  CAS  PubMed  Google Scholar 

  16. Gjerdrum LM, Woetmann A, Odum N et al (2007) FOXP3+ regulatory T cells in cutaneous T-cell lymphomas: association with disease stage and survival. Leukemia 21:2512–2518

    Article  CAS  PubMed  Google Scholar 

  17. Lee NR, Song EK, Jang KY et al (2008) Prognostic impact of tumor infiltrating FOXP3 positive regulatory T cells in diffuse large B-cell lymphoma at diagnosis. Leuk Lymphoma 49:247–256

    Article  CAS  PubMed  Google Scholar 

  18. Mourmouras V, Fimiani M, Rubegni P et al (2007) Evaluation of tumour-infiltrating CD4+CD25+FOXP3+ regulatory T cells in human cutaneous benign and atypical naevi, melanomas and melanoma metastases. Br J Dermatopathol 157:531–539

    Article  CAS  Google Scholar 

  19. De Panfilis G, Campanini N, Santini M et al (2008) Phase- and stage-related proportions of T cells bearing the transcription factor FOXP3 infiltrate primary melanoma. J Invest Dermatol 128:676–684

    PubMed  Google Scholar 

  20. Miracco C, Mourmouras V, Biagioli M et al (2007) Utility of tumour-infiltrating CD25+FOXP3+ regulatory T cell evaluation in predicting local recurrence in vertical growth phase cutaneous melanoma. Oncol Rep 18:1115–1122

    PubMed  Google Scholar 

  21. Hillen F, Baeten CIM, van de Winkel A et al (2008) Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 57:97–106

    Article  PubMed  Google Scholar 

  22. Ladányi A, Somlai B, Gilde K et al (2004) T-cell activation marker expression on tumor-infiltrating lymphocytes as prognostic factor in cutaneous malignant melanoma. Clin Cancer Res 10:521–530

    Article  PubMed  Google Scholar 

  23. Ladányi A, Kiss J, Somlai B et al (2007) Density of DC-LAMP+ mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor. Cancer Immunol Immunother 56:1459–1469

    Article  PubMed  Google Scholar 

  24. Balch CM, Buzaid AC, Soong S-J et al (2001) Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648

    CAS  PubMed  Google Scholar 

  25. Ebert LM, Tan BS, Browning J et al (2008) The regulatory T cell-associated transcription factor FOXP3 is expressed by tumor cells. Cancer Res 68:3001–3009

    Article  CAS  PubMed  Google Scholar 

  26. Morgan ME, van Bilsen JH, Bakker AM et al (2005) Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. Hum Immunol 66:13–20

    Article  CAS  PubMed  Google Scholar 

  27. Roncador G, Brown PJ, Maestre L et al (2005) Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur J Immunol 35:1681–1691

    Article  CAS  PubMed  Google Scholar 

  28. Wang J, Ioan-Facsinay A, van der Voort EI et al (2007) Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 37:129–138

    Article  CAS  PubMed  Google Scholar 

  29. Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336

    Article  CAS  PubMed  Google Scholar 

  30. Fontenot JD, Rasmussen JP, Williams LM et al (2005) Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22:329–341

    Article  CAS  PubMed  Google Scholar 

  31. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061

    Article  CAS  PubMed  Google Scholar 

  32. Yagi H, Nomura T, Nakamura K et al (2004) Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Int Immunol 16:1643–1656

    Article  CAS  PubMed  Google Scholar 

  33. Walker MR, Kasprowicz DJ, Gersuk VH et al (2003) Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25− T cells. J Clin Invest 112:1437–1443

    CAS  PubMed  Google Scholar 

  34. Allan SE, Passerini L, Bacchetta R et al (2005) The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J Clin Invest 115:3276–3284

    Article  CAS  PubMed  Google Scholar 

  35. Allan SE, Crome SQ, Crellin NK et al (2007) Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 19:345–354

    Article  CAS  PubMed  Google Scholar 

  36. Ziegler SF (2006) FOXP3: of mice and men. Annu Rev Immunol 24:209–226

    Article  CAS  PubMed  Google Scholar 

  37. Kryczek I, Liu R, Wang G et al (2009) FOXP3 defines regulatory T cells in human tumor and autoimmune disease. Cancer Res 69:3995–4000

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Katalin Derecskei, Ibolya Sinka and Miklós Kónya (National Institute of Oncology) for their excellent technical assistance. The study was supported by Hungarian Ministry of Health grant ETT 308/2003 (AL), Hungarian Scientific Research Fund grant OTKA K 72836 (AL), and NKFP1a-0024-05 (JT).

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Authors and Affiliations

  1. Center of Surgical and Molecular Tumor Pathology, National Institute of Oncology, 7–9. Ráth György u., Budapest, 1122, Hungary

    Andrea Ladányi

  2. Department of Dermatology, National Institute of Oncology, Budapest, Hungary

    Gabriella Liszkay, Katalin Gilde & Zsuzsanna Fejős

  3. National Cancer Registry, National Institute of Oncology, Budapest, Hungary

    István Gaudi

  4. Institute of Dermato-Venerology, Semmelweis University, Budapest, Hungary

    Beáta Somlai

  5. 1st Institute of Pathology, Semmelweis University, Budapest, Hungary

    Anita Mohos

  6. 2nd Institute of Pathology, Semmelweis University, Budapest, Hungary

    József Tímár

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  1. Andrea Ladányi
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  2. Anita Mohos
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  3. Beáta Somlai
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Correspondence to Andrea Ladányi.

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Ladányi, A., Mohos, A., Somlai, B. et al. FOXP3+ Cell Density in Primary Tumor Has No Prognostic Impact in Patients with Cutaneous Malignant Melanoma. Pathol. Oncol. Res. 16, 303–309 (2010). https://doi.org/10.1007/s12253-010-9254-x

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  • DOI: https://doi.org/10.1007/s12253-010-9254-x

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