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Journal of Cancer Research and Clinical Oncology

Erschienen in:

01.11.2012 | Original Paper

Increased number of regulatory T cells (T-regs) in the peripheral blood of patients with Her-2/neu-positive early breast cancer

verfasst von: Thomas Decker, Gerhard Fischer, Wolfgang Bücke, Philipp Bücke, Frank Stotz, Andreas Grüneberger, Martina Gropp-Meier, Günther Wiedemann, Christine Pfeiffer, Christian Peschel, Katharina Götze

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 11/2012

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Abstract

Background

Although progress has been made in establishing prognostic factors in breast cancer, there remains an urgent need for better prognostic and predictive scores for patients with early breast cancer. The important role of the immune system in controlling cancer progression is widely accepted. Regulatory T cells (T-regs) constitute a specialized T cell subset, which play an essential role in sustaining self-tolerance by negatively regulating immune responses. Increased frequencies of T-regs have been reported in the micromilieu of a variety of malignancies including breast cancer. However, little is known about the role of T-regs in the peripheral blood of cancer patients.

Methods

We analyzed T-reg numbers in the peripheral blood of 292 patients with newly diagnosed early breast cancer by flow cytometry (CD4⁺CD25⁺CD127^low cells) prior to planned breast surgery.

Results

Absolute T-reg numbers/µl varied from 4 to 212/µl. No difference could be detected in T-reg numbers between nodal negative and nodal positive, well and poorly differentiated or small and locally advanced cancers. However, T-reg numbers of Her-2/neu-positive patients were higher than in samples from patients with hormone receptor positive, Her-2/neu-negative cancers. In contrast, numbers of T-regs were not increased in triple negative patients. In addition, T-reg numbers were higher in patients with invasive ductal carcinomas as compared to invasive lobular cancers.

Conclusions

Increased numbers of circulating T-regs may contribute to the higher metastatic potential of Her-2/neu-positive cells. A potential role as a prognostic or predictive parameter is currently being analyzed in a larger cohort of patients with sufficient follow-up.

Ardon H, Verbinnen B, Maes W, Beez T, Van Gool S, De Vleeschouwer S (2010) Technical advancement in regulatory T cell isolation and characterization using CD127 expression in patients with malignant glioma treated with autologous dendritic cell vaccination. J Immunol Methods 352:169–173PubMedCrossRef

Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, Banham AH (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 24:5373–5380PubMedCrossRef

Baxevanis CN, Voutsas IF, Gritzapis AD, Perez SA, Papamichail M (2010) HER-2/neu as a target for cancer vaccines. Immunotherapy 2:213–226PubMedCrossRef

Benson JR, Jatoi I, Keisch M, Esteva FJ, Makris A, Jordan VC (2009) Early breast cancer. Lancet 373:1463–1479PubMedCrossRef

Beyer M, Schultze JL (2006) Regulatory T cells in cancer. Blood 108:804–811PubMedCrossRef

Beyer M, Kochanek M, Giese T, Endl E, Weihrauch MR, Knolle PA, Classen S, Schultze JL (2006) In vivo peripheral expansion of naive CD4+ CD25high FoxP3+ regulatory T cells in patients with multiple myeloma. Blood 107:3940–3949PubMedCrossRef

Clarke SL, Betts GJ, Plant A, Wright KL, El-Shanawany TM, Harrop R, Torkington J, Rees BI, Williams GT, Gallimore AM, Godkin AJ (2006) CD4+ CD25+ FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS One 1:e129PubMedCrossRef

Colombo MP, Piconese S (2007) Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nat Rev Cancer 7:880–887PubMedCrossRef

Ebert LM, Tan BS, Browning J, Svobodova S, Russell SE, Kirkpatrick N, Gedye C, Moss D, Ng SP, MacGregor D, Davis ID, Cebon J, Chen W (2008) The regulatory T cell-associated transcription factor FoxP3 is expressed by tumor cells. Cancer Res 68:3001–3009PubMedCrossRef

Emens LA (2012) Re-purposing cancer therapeutics for breast cancer immunotherapy. Cancer Immunol Immunother [Epub ahead of print]

Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, Biota C, Doffin AC, Durand I, Olive D, Perez S, Pasqual N, Faure C, Ray-Coquard I, Puisieux A, Caux C, Blay JY, Menetrier-Caux C (2009) Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res 69:2000–2009PubMedCrossRef

Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ (2009) Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol 20:1319–1329PubMedCrossRef

Grant J, Bourcier K, Wallace S, Pan D, Conway A, Seyfert-Margolis V, Wallace PK (2009) Validated protocol for FoxP3 reveals increased expression in type 1 diabetes patients. Cytometry B Clin Cytom 76:69–78PubMed

Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899PubMedCrossRef

Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC (2010) American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28:2784–2795PubMedCrossRef

Iorfida M, Maiorano E, Orvieto E, Maisonneuve P, Bottiglieri L, Rotmensz N, Montagna E, Dellapasqua S, Veronesi P, Galimberti V, Luini A, Goldhirsch A, Colleoni M, Viale G (2012) Invasive lobular breast cancer: subtypes and outcome. Breast Cancer Res Treat 133(2):713–723

Li CI, Moe RE, Daling JR (2003) Risk of mortality by histologic type of breast cancer among women aged 50 to 79 years. Arch Intern Med 163:2149–2153PubMedCrossRef

Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, Clayberger C, Soper DM, Ziegler SF, Bluestone JA (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+T reg cells. J Exp Med 203:1701–1711

Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756–2761PubMed

Lu H (2009) FOXP3 expression and prognosis: role of both the tumor and T cells. J Clin Oncol 27:1735–1736PubMedCrossRef

Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Lee AH, Ellis IO, Green AR (2011) An evaluation of the clinical significance of FOXP3(+) infiltrating cells in human breast cancer. Breast Cancer Res Treat 127:99–108PubMedCrossRef

Menetrier-Caux C, Gobert M, Caux C (2009) Differences in tumor regulatory T-cell localization and activation status impact patient outcome. Cancer Res 69:7895–7898PubMedCrossRef

Merlo A, Casalini P, Carcangiu ML, Malventano C, Triulzi T, Menard S, Tagliabue E, Balsari A (2009) FOXP3 expression and overall survival in breast cancer. J Clin Oncol 27:1746–1752PubMedCrossRef

Nakamura R, Sakakibara M, Nagashima T, Sangai T, Arai M, Fujimori T, Takano S, Shida T, Nakatani Y, Miyazaki M (2009) Accumulation of regulatory T cells in sentinel lymph nodes is a prognostic predictor in patients with node-negative breast cancer. Eur J Cancer 45:2123–2131PubMedCrossRef

Olkhanud PB, Baatar D, Bodogai M, Hakim F, Gress R, Anderson RL, Deng J, Xu M, Briest S, Biragyn A (2009) Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells. Cancer Res 69:5996–6004PubMedCrossRef

Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C, Fridman WH (2000) Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 29:1093–1102

Sauter G, Lee J, Bartlett JM, Slamon DJ, Press MF (2009) Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations. J Clin Oncol 27:1323–1333PubMedCrossRef

Sellitto A, Galizia G, De Fanis U, Lieto E, Zamboli A, Orditura M, De Vita F, Giunta R, Lucivero G, Romano C (2011) Behavior of circulating CD4+ CD25+ Foxp3+ regulatory T cells in colon cancer patients undergoing surgery. J Clin Immunol 31:1095–1104PubMedCrossRef

Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, DeMarzo AM, Meeker AK, Isaacs WB, Drake CG (2008) Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res 14:3254–3261PubMedCrossRef

Sotiriou C, Pusztai L (2009) Gene-expression signatures in breast cancer. N Engl J Med 360:790–800PubMedCrossRef

Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, Karin M (2011) Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470:548–553PubMedCrossRef

Watanabe MA, Oda JM, Amarante MK, Cesar Voltarelli J (2010) Regulatory T cells and breast cancer: implications for immunopathogenesis. Cancer Metastasis Rev 29:569–579PubMedCrossRef

Wilke CM, Wu K, Zhao E, Wang G, Zou W (2010) Prognostic significance of regulatory T cells in tumor. Int J Cancer 127:748–758PubMed

Wing K, Sakaguchi S (2010) Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 11:7–13

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 9:606–612PubMed

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

Zou L, Barnett B, Safah H, Larussa VF, Evdemon-Hogan M, Mottram P, Wei S, David O, Curiel TJ, Zou W (2004) Bone marrow is a reservoir for CD4+ CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res 64:8451–8455PubMedCrossRef

Titel: Increased number of regulatory T cells (T-regs) in the peripheral blood of patients with Her-2/neu-positive early breast cancer
verfasst von: Thomas Decker
Gerhard Fischer
Wolfgang Bücke
Philipp Bücke
Frank Stotz
Andreas Grüneberger
Martina Gropp-Meier
Günther Wiedemann
Christine Pfeiffer
Christian Peschel
Katharina Götze
Publikationsdatum: 01.11.2012
Verlag: Springer-Verlag
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 11/2012
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-012-1258-3

Springer Medizin

Increased number of regulatory T cells (T-regs) in the peripheral blood of patients with Her-2/neu-positive early breast cancer