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An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer

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Abstract

Studies in mice have shown that thymic-derived CD4+ CD25+ regulatory T cells (T reg; FOXP3+ lymphocytes) inhibit an antitumour immune response. Additional studies have also reported that the T reg population increases in peripheral blood and tumour tissues from patients with cancer. However, the relationship between the T reg population and the patient prognosis remains controversial. Our aim was to determine the prognostic value of T reg cell density in breast cancer using immunohistochemical assessment of FOXP3, which has been shown to be the optimal marker for T regs. Tissue microarrays were used, and the density of FOXP3+ cells was determined in a series of 1445 cases of well-characterised primary invasive breast carcinoma cases with long-term follow up. FOXP3+ cell numbers were counted in tumour nests, in tumour-adjacent stroma, and in distant stroma. The total number of FOXP3+ cells significantly correlated with higher tumour grade (r s = 0.37, P < 0.001) and ER negativity (Mann–Whitney U test, P < 0.001). In addition, FOXP3 infiltration positively correlated with HER2 expression and basal phenotype subclass. On univariate analysis, FOXP3+ cells were associated with a worse prognosis (P = 0.012, log rank = 6.36). This association was found for intratumoural FOXP3+ and for tumour-adjacent stromal FOXP3+-cells (tumour-cell associated FOXP3, P = 0.001 and log rank 10.35). However, the number of FOXP3+ cells was not found to be an independent prognostic factor in multivariate analysis. We therefore conclude that FOXP3+ infiltrating cells do not have a dominant role in breast cancer prognosis and suggest that other inflammatory cell subsets may be more critical variables.

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References

  1. Callagy G, Cattaneo E, Daigo Y, Happerfield L, Bobrow LG, Pharoah PD et al (2003) Molecular classification of breast carcinomas using tissue microarrays. Diagn Mol Pathol 12(1):27–34

    Article  PubMed  CAS  Google Scholar 

  2. Stewart TH, Heppner GH (1997) Immunological enhancement of breast cancer. Parasitology 115:S141–S153

    Article  PubMed  Google Scholar 

  3. Lee AH, Gillett CE, Ryder K, Fentiman IS, Miles DW, Millis RR (2006) Different patterns of inflammation and prognosis in invasive carcinoma of the breast. Histopathology 48(6):692–701

    Article  PubMed  CAS  Google Scholar 

  4. Rilke F, Colnaghi MI, Cascinelli N, Andreola S, Baldini MT, Bufalino R et al (1991) Prognostic significance of HER-2/neu expression in breast cancer and its relationship to other prognostic factors. Int J Cancer 49(1):44–49

    Article  PubMed  CAS  Google Scholar 

  5. Carlomagno C, Perrone F, Lauria R, de Laurentiis M, Gallo C, Morabito A et al (1995) Prognostic significance of necrosis, elastosis, fibrosis and inflammatory cell reaction in operable breast cancer. Oncology 52(4):272–277

    Article  PubMed  CAS  Google Scholar 

  6. Yu P, Fu YX (2006) Tumor-infiltrating T lymphocytes: friends or foes? Lab Invest 86(3):231–245

    Article  PubMed  CAS  Google Scholar 

  7. Sprent J, Surh CD (2003) Knowing one’s self: central tolerance revisited. Nat Immunol 4(4):303–304

    Article  PubMed  CAS  Google Scholar 

  8. Curiel TJ (2007) Tregs and rethinking cancer immunotherapy. J Clin Invest 117(5):1167–1174

    Article  PubMed  CAS  Google Scholar 

  9. Buckner JH, Ziegler SF (2004) Regulating the immune system: the induction of regulatory T cells in the periphery. Arthritis Res Ther 6(5):215–222

    Article  PubMed  CAS  Google Scholar 

  10. Kosmaczewska A, Ciszak L, Potoczek S, Frydecka I (2008) The significance of Treg cells in defective tumor immunity. Arch Immunol Ther Exp (Warsz) 56(3):181–191

    Article  CAS  Google Scholar 

  11. Ramsdell F (2003) Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity 19(2):165–168

    Article  PubMed  CAS  Google Scholar 

  12. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G (2001) Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med 193(11):1303–1310

    Article  PubMed  CAS  Google Scholar 

  13. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G et al (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169(5):2756–2761

    PubMed  CAS  Google Scholar 

  14. Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101(5):455–458

    Article  PubMed  CAS  Google Scholar 

  15. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22(3):329–341

    Article  PubMed  CAS  Google Scholar 

  16. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061

    Article  PubMed  CAS  Google Scholar 

  17. Roncador G, Brown PJ, Maestre L, Hue S, Martinez-Torrecuadrada JL, Ling KL et al (2005) Analysis of FOXP3 protein expression in human CD4+ CD25+ regulatory T cells at the single-cell level. Eur J Immunol 35(6):1681–1691

    Article  PubMed  CAS  Google Scholar 

  18. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59(13):3128–3133

    PubMed  CAS  Google Scholar 

  19. Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+ CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163(10):5211–5218

    PubMed  CAS  Google Scholar 

  20. Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP et al (2001) Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 194(6):823–832

    Article  PubMed  CAS  Google Scholar 

  21. Tanaka H, Tanaka J, Kjaergaard J, Shu S (2002) Depletion of CD4+ CD25+ regulatory cells augments the generation of specific immune T cells in tumor-draining lymph nodes. J Immunother 25(3):207–217

    Article  PubMed  CAS  Google Scholar 

  22. Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL 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(34):5373–5380

    Article  PubMed  Google Scholar 

  23. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10(9):942–949

    Article  PubMed  CAS  Google Scholar 

  24. Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B (2003) Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9(2):606–612

    PubMed  Google Scholar 

  25. 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(18):5423–5434

    Article  PubMed  CAS  Google Scholar 

  26. Petersen RP, Campa MJ, Sperlazza J, Conlon D, Joshi MB, Harpole DH Jr et al (2006) Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer 107(12):2866–2872

    Article  PubMed  Google Scholar 

  27. Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS et al (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25(18):2586–2593

    Article  PubMed  Google Scholar 

  28. Yoshioka T, Miyamoto M, Cho Y, Ishikawa K, Tsuchikawa T, Kadoya M et al (2008) Infiltrating regulatory T cell numbers is not a factor to predict patient’s survival in oesophageal squamous cell carcinoma. Br J Cancer 98(7):1258–1263

    Article  PubMed  CAS  Google Scholar 

  29. Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D et al (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27(2):186–192

    Article  PubMed  Google Scholar 

  30. Ladoire S, Arnould L, Apetoh L, Coudert B, Martin F, Chauffert B et al (2008) Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells. Clin Cancer Res 14(8):2413–2420

    Article  PubMed  CAS  Google Scholar 

  31. Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JF et al (2005) High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer 116(3):340–350

    Article  PubMed  CAS  Google Scholar 

  32. Abd El-Rehim DM, Pinder SE, Paish CE, Bell J, Blamey RW, Robertson JF et al (2004) Expression of luminal and basal cytokeratins in human breast carcinoma. J Pathol 203(2):661–671

    Article  PubMed  Google Scholar 

  33. Rakha EA, El-Rehim DA, Paish C, Green AR, Lee AH, Robertson JF et al (2006) Basal phenotype identifies a poor prognostic subgroup of breast cancer of clinical importance. Eur J Cancer 42(18):3149–3156

    Article  PubMed  CAS  Google Scholar 

  34. Zhang H, Rakha EA, Ball GR, Spiteri I, Aleskandarany M, Paish EC et al (2010) The proteins FABP7 and OATP2 are associated with the basal phenotype and patient outcome in human breast cancer. Breast Cancer Res Treat 121(1):41–51

    Article  PubMed  CAS  Google Scholar 

  35. Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19(5):403–410

    Article  PubMed  CAS  Google Scholar 

  36. Ellis IO, Galea M, Broughton N, Locker A, Blamey RW, Elston CW (1992) Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow-up. Histopathology 20(6):479–489

    Article  PubMed  CAS  Google Scholar 

  37. Pinder SE, Ellis IO, Galea M, O’Rouke S, Blamey RW, Elston CW (1994) Pathological prognostic factors in breast cancer. III. Vascular invasion: relationship with recurrence and survival in a large study with long-term follow-up. Histopathology 24(1):41–47

    Article  PubMed  CAS  Google Scholar 

  38. Galea MH, Blamey RW, Elston CE, Ellis IO (1992) The Nottingham Prognostic Index in primary breast cancer. Breast Cancer Res Treat 22(3):207–219

    Article  PubMed  CAS  Google Scholar 

  39. Green AR, Burney C, Granger CJ, Paish EC, El-Sheikh S, Rakha EA et al (2008) The prognostic significance of steroid receptor co-regulators in breast cancer: co-repressor NCOR2/SMRT is an independent indicator of poor outcome. Breast Cancer Res Treat 110(3):427–437

    Article  PubMed  CAS  Google Scholar 

  40. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23(36):9067–9072

    Article  PubMed  Google Scholar 

  41. Rakha EA, El-Sheikh SE, Kandil MA, El-Sayed ME, Green AR, Ellis IO (2008) Expression of BRCA1 protein in breast cancer and its prognostic significance. Hum Pathol 39(6):857–865

    Article  PubMed  CAS  Google Scholar 

  42. Camp RL, Dolled-Filhart M, Rimm DL (2004) X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 10(21):7252–7259

    Article  PubMed  CAS  Google Scholar 

  43. Dolled-Filhart M, McCabe A, Giltnane J, Cregger M, Camp RL, Rimm DL (2006) Quantitative in situ analysis of beta-catenin expression in breast cancer shows decreased expression is associated with poor outcome. Cancer Res 66(10):5487–5494

    Article  PubMed  CAS  Google Scholar 

  44. Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO (2007) Prognostic markers in triple-negative breast cancer. Cancer 109(1):25–32

    Article  PubMed  CAS  Google Scholar 

  45. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155(3):1151–1164

    PubMed  CAS  Google Scholar 

  46. Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6(4):295–307

    Article  PubMed  CAS  Google Scholar 

  47. Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay Nel H et al (2006) Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12(2):465–472

    Article  PubMed  CAS  Google Scholar 

  48. Carreras J, Lopez-Guillermo A, Fox BC, Colomo L, Martinez A, Roncador G et al (2006) High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood 108(9):2957–2964

    Article  PubMed  CAS  Google Scholar 

  49. Wolf D, Wolf AM, Rumpold H, Fiegl H, Zeimet AG, Muller-Holzner E et al (2005) The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 11(23):8326–8331

    Article  PubMed  CAS  Google Scholar 

  50. Grabenbauer GG, Lahmer G, Distel L, Niedobitek G (2006) Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. Clin Cancer Res 12(11 Pt 1):3355–3360

    Article  PubMed  CAS  Google Scholar 

  51. Bohling SD, Allison KH (2008) Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target. Mod Pathol 21(12):1527–1532

    Article  PubMed  CAS  Google Scholar 

  52. Ghebeh H, Barhoush E, Tulbah A, Elkum N, Al-Tweigeri T, Dermime S (2008) FOXP3+ Tregs and B7–H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy. BMC Cancer 8:57

    Article  PubMed  Google Scholar 

  53. Ahmadzadeh M, Felipe-Silva A, Heemskerk B, Powell DJ Jr, Wunderlich JR, Merino MJ et al (2008) FOXP3 expression accurately defines the population of intratumoral regulatory T cells that selectively accumulate in metastatic melanoma lesions. Blood 112(13):4953–4960

    Article  PubMed  CAS  Google Scholar 

  54. Hinz S, Pagerols-Raluy L, Oberg HH, Ammerpohl O, Grussel S, Sipos B et al (2007) Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res 67(17):8344–8350

    Article  PubMed  CAS  Google Scholar 

  55. Karanikas V, Speletas M, Zamanakou M, Kalala F, Loules G, Kerenidi T et al (2008) Foxp3 expression in human cancer cells. J Transl Med 6:19

    Article  PubMed  Google Scholar 

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Acknowledgement

Sahar M. A. Mahmoud would like to thank the Egyptian Ministry of Higher Education for funding her during this work.

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Authors and Affiliations

  1. Division of Pathology, School of Molecular Medical Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham, NG7 2UH, UK

    Sahar M. A. Mahmoud, Ian O. Ellis & Andrew R. Green

  2. Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt

    Sahar M. A. Mahmoud

  3. Department of Histopathology, Nottingham University Hospitals NHS Trust, Nottingham, UK

    Emma C. Paish, Desmond G. Powe, Andrew H. S. Lee & Ian O. Ellis

  4. The Breast Institute, Nottingham University Hospitals NHS Trust, Nottingham, UK

    R. Douglas Macmillan

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  1. Sahar M. A. Mahmoud
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Correspondence to Andrew R. Green.

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Mahmoud, S.M.A., Paish, E.C., Powe, D.G. et al. An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer. Breast Cancer Res Treat 127, 99–108 (2011). https://doi.org/10.1007/s10549-010-0987-8

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  • DOI: https://doi.org/10.1007/s10549-010-0987-8

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