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In Reply

Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom

There are currently several studies demonstrating the clinical significance of regulatory T cell (Treg) numbers in a range of malignancies and the importance of forkhead box protein P3 (FOXP3) as a Treg marker. The novel findings in our study of the clinical significance of Treg numbers in breast cancer are that high Treg numbers identify a subpopulation of patients with an unfavorable outcome, even those within the good prognosis estrogen receptor–positive group and also patients at risk of late relapse.¹

The correspondence by Ferretti cites data from a study by Hoffmann et al² describing the altered phenotype of in vitro expanded CD4⁺CD25^high T cells from human peripheral blood as their reason for agreeing that FOXP3-positive Treg represent an important therapeutic target for breast cancer. While these data highlight an important point regarding adoptive transfer of in vitro expanded Treg, we would like to clarify that our recent study¹ does not indicate the adoptive transfer of Treg for patients with breast cancer. In contrast, our study suggests that strategies to deplete the high numbers (or ablate Treg function) of Treg in vivo may prove beneficial to a significant proportion of breast cancer patients.

We agree with Ferretti that targeting FOXP3-positive Tregs is important. We have previously described human FOXP3⁺CD25^– and FOXP3⁺CD8⁺ T cell populations and the existence of a significant number of FOXP3⁺ T cells within the CD4⁺CD25^int subpopulation³; highlighting limitations of relying on a CD4⁺CD25^high phenotype alone. However, as an intracellular molecule, FOXP3 cannot be used to isolate functional Tregs or target in vivo monoclonal antibody–based depletion strategies. Recent studies using a lack of or low-level of CD127 expression to distinguish Tregs from CD127⁺ activated T cells have enabled the purification and functional characterization of a broader human Treg population, including those lacking CD25 expression.^4,5 These studies have further confirmed the importance of FOXP3 as a Treg marker and therapeutic target. Strategies to specifically manipulate FOXP3 expression or function and/or reduce Treg numbers, together with the search for additional Treg cell surface markers have exciting implications for immunotherapy of breast cancer and other malignancies.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Bates GJ, Fox SB, Han C, et al: 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, 2006[Abstract/Free Full Text]

2. Hoffmann P, Eder R, Boeld TJ, et al: Only the CD45RA⁺ subpopulation of CD4⁺CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood 108:4260-4267, 2006[Abstract/Free Full Text]

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

4. Seddiki N, Santner-Nanan B, Martinson J, et al: Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 203:1693-1700, 2006[Abstract/Free Full Text]

5. Liu W, Putnam AL, Xu-Yu Z, et al: CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4⁺ T reg cells. J Exp Med 203:1701-1711, 2006[CrossRef][Medline]

Related Correspondence

• Forkhead Box P3-Positive Regulatory T Cells As Therapeutic Target for Breast Cancer
  Gianluigi Ferretti
  JCO 2007 25: 29 [Full Text]

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