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Published in:

01-12-2010

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

Authors: Mansooreh Jaberipour, Mojtaba Habibagahi, Ahmad Hosseini, Saadat Rezai Habibabad, Abdolrasoul Talei, Abbas Ghaderi

Published in: Pathology & Oncology Research | Issue 4/2010

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.

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 145:505–509PubMed

Elgert KD, Alleva DG, Mullins DW (1998) Tumor-induced immune dysfunction: the macrophage connection. J Leukoc Biol 64:275–290PubMed

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 95:1178–1183CrossRefPubMed

Roncarolo MG, Gregori S, Levings M (2003) Type 1 T regulatory cells and their relationship with CD4+CD25+ T regulatory cells. Novartis Found Symp 252:115–127CrossRefPubMed

Caras I, Grigorescu A, Stavaru C et al (2004) Evidence for immune defects in breast and lung cancer patients. Cancer Immunol Immunother 53:1146–1152CrossRefPubMed

Wolf AM, Wolf D, Steurer M et al (2003) Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9:606–612PubMed

O’Garra A, Vieira P (2004) Regulatory T cells and mechanisms of immune system control. Nat Med 10:801–805CrossRefPubMed

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

Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352CrossRefPubMed

10.

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

11.

Fontenot JD, Rasmussen JP, Williams LM et al (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329–341CrossRefPubMed

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 61:4766–4772PubMed

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 169:2756–2761PubMed

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 173:1444–1453PubMed

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 65:2457–2464CrossRefPubMed

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:e129CrossRefPubMed

17.

Gallimore A, Godkin A (2008) Regulatory T cells and tumour immunity—observations in mice and men. Immunology 123:157–163CrossRefPubMed

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 13:6301–6311CrossRefPubMed

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 ChineasePubMed

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 58:441–447CrossRefPubMed

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 9:231CrossRefPubMed

22.

Merlo A, Casalini P, Carcangiu ML et al (2009) FOXP3 expression and overall survival in breast cancer. J Clin Oncol 27:1746–1752CrossRefPubMed

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 46:792–797CrossRefPubMed

24.

Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45CrossRefPubMed

25.

Shevach EM, McHugh RS, Piccirillo CA et al (2001) Control of T-cell activation by CD4+ CD25+ suppressor T cells. Immunol Rev 182:58–67CrossRefPubMed

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 36:629–648CrossRefPubMed

27.

Brusko TM, Hulme MA, Myhr CB et al (2007) Assessing the in vitro suppressive capacity of regulatory T cells. Immunol Invest 36:607–628CrossRefPubMed

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 49:1190–1201CrossRefPubMed

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 67:5929–5939CrossRefPubMed

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 106:1227–1236CrossRefPubMed

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 24:5373–5380CrossRefPubMed

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 100:4712–4717CrossRefPubMed

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 100:8372–8377CrossRefPubMed

Title: Increased CTLA-4 and FOXP3 Transcripts in Peripheral Blood Mononuclear Cells of Patients with Breast Cancer
Authors: Mansooreh Jaberipour
Mojtaba Habibagahi
Ahmad Hosseini
Saadat Rezai Habibabad
Abdolrasoul Talei
Abbas Ghaderi
Publication date: 01-12-2010
Publisher: Springer Netherlands
Published in: Pathology & Oncology Research / Issue 4/2010
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI: https://doi.org/10.1007/s12253-010-9256-8

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