Pathology & Oncology Research

, Volume 16, Issue 4, pp 547–551 | Cite as

Increased CTLA-4 and FOXP3 Transcripts in Peripheral Blood Mononuclear Cells of Patients with Breast Cancer

  • Mansooreh Jaberipour
  • Mojtaba Habibagahi
  • Ahmad Hosseini
  • Saadat Rezai Habibabad
  • Abdolrasoul Talei
  • Abbas Ghaderi
Article

Abstract

Generation of Regulatory T cells (Tregs) is known to play a major role in progression and modulation of the immune escape mechanisms in cancer. These cells express Forkhead/winged helix transcription factor (FOXP3) and also Cytotoxic T-lymphocyte antigen-4 (CTLA-4), as a negative regulatory molecule which, is a potential target for immunotherapy. We, therefore, evaluated FOXP3 and CTLA-4 transcripts in the peripheral blood mononuclear cells from 55 women with histologically-confirmed infiltrating ductal carcinoma of the breast. Blood samples from 40 healthy volunteer women without a history of malignancies or autoimmune disorders were also obtained as a control. The abundance of FOXP3 and CTLA-4 gene transcripts was determined by quantitative real-time PCR (qRT-PCR). Compared to healthy individuals, significantly higher amounts of these transcripts were found in the mononuclear cells from breast cancer patients. Also, a significant correlation was found between CTLA-4 and FOXP3 expressions in a group of patients. Among patients with early stage, nonmetastatic or low-grade disease, the relative expression of CTLA-4 was about 10-fold as much as in the control group. These patients also showed a significant increase, more than 10 fold, in mean relative FOXP3 expression. The results of this investigation point to functional activity of Treg cells in early stages of breast cancer, a finding which emphasizes the significance of Tregs as an imminent target for breast cancer immunotherapy.

Keywords

Breast cancer CTLA-4 and FOXP3 

Abbreviations

CTLA-4

Cytotoxic T-lymphocyte antigen-4

GITR

Glucocorticoid-induced tumor necrosis factor receptor

TGF-β

Τransforming growth factor- betta

FoxP3

Forkhead/winged helix transcription factor

qRT-PCR

quantitative real-time PCR

References

  1. 1.
    Kaklamanis L, Townsend A, Doussis-Anagnostopoulou IA et al (1994) Loss of major histocompatibility complex-encoded transporter associated with antigen presentation (TAP) in colorectal cancer. Am J Pathol 145:505–509PubMedGoogle Scholar
  2. 2.
    Elgert KD, Alleva DG, Mullins DW (1998) Tumor-induced immune dysfunction: the macrophage connection. J Leukoc Biol 64:275–290PubMedGoogle Scholar
  3. 3.
    Staveley-O’Carroll K, Sotomayor E, Montgomery J et al (1998) Induction of antigen-specific T cell anergy: an early event in the course of tumor progression. Proc Natl Acad Sci USA 95:1178–1183CrossRefPubMedGoogle Scholar
  4. 4.
    Roncarolo MG, Gregori S, Levings M (2003) Type 1 T regulatory cells and their relationship with CD4+CD25+ T regulatory cells. Novartis Found Symp 252:115–127CrossRefPubMedGoogle Scholar
  5. 5.
    Caras I, Grigorescu A, Stavaru C et al (2004) Evidence for immune defects in breast and lung cancer patients. Cancer Immunol Immunother 53:1146–1152CrossRefPubMedGoogle Scholar
  6. 6.
    Wolf AM, Wolf D, Steurer M et al (2003) Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9:606–612PubMedGoogle Scholar
  7. 7.
    O’Garra A, Vieira P (2004) Regulatory T cells and mechanisms of immune system control. Nat Med 10:801–805CrossRefPubMedGoogle Scholar
  8. 8.
    Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101:455–458CrossRefPubMedGoogle Scholar
  9. 9.
    Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352CrossRefPubMedGoogle Scholar
  10. 10.
    Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061CrossRefPubMedGoogle Scholar
  11. 11.
    Fontenot JD, Rasmussen JP, Williams LM et al (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329–341CrossRefPubMedGoogle Scholar
  12. 12.
    Woo EY, Chu CS, Goletz TJ et al (2001) Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61:4766–4772PubMedGoogle Scholar
  13. 13.
    Liyanage UK, Moore TT, Joo HG 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 169:2756–2761PubMedGoogle Scholar
  14. 14.
    Viguier M, Lemaitre F, Verola O et al (2004) Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol 173:1444–1453PubMedGoogle Scholar
  15. 15.
    Ormandy LA, Hillemann T, Wedemeyer H et al (2005) Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 65:2457–2464CrossRefPubMedGoogle Scholar
  16. 16.
    Clarke SL, Betts GJ, Plant A et al (2006) CD4+CD25+FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoSONE 1:e129CrossRefPubMedGoogle Scholar
  17. 17.
    Gallimore A, Godkin A (2008) Regulatory T cells and tumour immunity—observations in mice and men. Immunology 123:157–163CrossRefPubMedGoogle Scholar
  18. 18.
    Strauss L, Bergmann C, Gooding W et al (2007) The frequency and suppressor function of CD4+CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck. Clin Cancer Res 13:6301–6311CrossRefPubMedGoogle Scholar
  19. 19.
    Bi Y, Wei L, Mao HT, Zhang L, Zuo WS (2008) Expressions of Fas, CTLA-4 and RhoBTB2 genes in breast carcinoma and their relationship with clinicopathological factors. Zhonghua ZhongLiu Za Zhi 30:749–753, Article in ChineasePubMedGoogle Scholar
  20. 20.
    Ohara M, Yamaguchi Y, Matsuura K et al (2009) Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer Immunol Immunother 58:441–447CrossRefPubMedGoogle Scholar
  21. 21.
    Mansfield AS, Heikkila PS, Vaara AT et al (2009) Simultaneous Foxp3 and IDO expression is associated with sentinel lymph node metastases in breast cancer. BMC Cancer 9:231CrossRefPubMedGoogle Scholar
  22. 22.
    Merlo A, Casalini P, Carcangiu ML et al (2009) FOXP3 expression and overall survival in breast cancer. J Clin Oncol 27:1746–1752CrossRefPubMedGoogle Scholar
  23. 23.
    Gupta S, Joshi K, Wig JD, Arora SK (2007) Intratumoral FOXP3 expression in infiltrating breast carcinoma: its association with clinicopathologic parameters and angiogenesis. Acta Oncol 46:792–797CrossRefPubMedGoogle Scholar
  24. 24.
    Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45CrossRefPubMedGoogle Scholar
  25. 25.
    Shevach EM, McHugh RS, Piccirillo CA et al (2001) Control of T-cell activation by CD4+ CD25+ suppressor T cells. Immunol Rev 182:58–67CrossRefPubMedGoogle Scholar
  26. 26.
    Hilchey SP, Bernstein SH (2007) Use of CFSE to monitor ex vivo regulatory T-cell suppression of CD4+ and CD8+ T-cell proliferation within unseparated mononuclear cells from malignant and non-malignant human lymph node biopsies. Immunol Invest 36:629–648CrossRefPubMedGoogle Scholar
  27. 27.
    Brusko TM, Hulme MA, Myhr CB et al (2007) Assessing the in vitro suppressive capacity of regulatory T cells. Immunol Invest 36:607–628CrossRefPubMedGoogle Scholar
  28. 28.
    Capriotti E, Vonderheid EC, Thoburn CJ et al (2008) Expression of T-plastin, FoxP3 and other tumor-associated markers by leukemic T-cells of cutaneous T-cell lymphoma. Leuk Lymphoma 49:1190–1201CrossRefPubMedGoogle Scholar
  29. 29.
    Tuve S, Chen BM, Liu Y et al (2007) Combination of tumor site-located CTL-associated antigen-4 blockade and systemic regulatory T-cell depletion induces tumor-destructive immune responses. Cancer Res 67:5929–5939CrossRefPubMedGoogle Scholar
  30. 30.
    Matsuura K, Yamaguchi Y, Ueno H et al (2006) Maturation of dendritic cells and T-cell responses in sentinel lymph nodes from patients with breast carcinoma. Cancer 106:1227–1236CrossRefPubMedGoogle Scholar
  31. 31.
    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 24:5373–5380CrossRefPubMedGoogle Scholar
  32. 32.
    Hodi FS, Mihm MC, Soiffer RJ et al (2003) Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA 100:4712–4717CrossRefPubMedGoogle Scholar
  33. 33.
    Phan GQ, Yang JC, Sherry RM et al (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372–8377CrossRefPubMedGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2010

Authors and Affiliations

  • Mansooreh Jaberipour
    • 1
  • Mojtaba Habibagahi
    • 2
  • Ahmad Hosseini
    • 1
  • Saadat Rezai Habibabad
    • 2
  • Abdolrasoul Talei
    • 1
    • 3
  • Abbas Ghaderi
    • 1
    • 4
  1. 1.Cancer Gene Therapy Laboratory, Shiraz Institute for Cancer ResearchShiraz University of Medical SciencesShirazIran
  2. 2.Immunotherapy Laboratory, Department of ImmunologyShiraz University of Medical SciencesShirazIran
  3. 3.Department of SurgeryShiraz University of Medical SciencesShirazIran
  4. 4.Department of ImmunologyShiraz University of Medical SciencesShirazIran

Personalised recommendations