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Forkhead Box P3-Positive Regulatory T Cells As Therapeutic Target for Breast Cancer

Division of Medical Oncology A, Regina Elena Cancer Institute, Rome, Italy

To the Editor:

In their article, Bates et al¹ conclude that high numbers of forkhead box P3 (FOXP3)-positive regulatory T (Treg) cells represent an important marker for the identification of breast cancer patients at risk of late relapse. Similarly, patients with stage I non–small-cell lung cancer who have a higher proportion of tumor FOXP3-positive Treg cells relative to tumor-infiltrating T-cell lymphocytes have a significantly higher risk of recurrence.² In pancreatic ductal carcinoma, a high prevalence of FOXP3-positive Treg cells seems to be a marker of poor prognosis.³

CD25+CD4+ Treg cells, which specifically express the transcription factor FOXP3, are involved in the maintenance of immunological self-tolerance and suppressive control of aberrant immune responses. In contrast, they may impede the development of effective immunity to autologous tumor cells.⁴ As recently reported,⁵ only CCR7- and L-selectin (CD62L) coexpressing cells within expanded CD4+ T cells with high CD25 expression levels (CD25^high) maintain phenotypic and functional characteristics of Treg cells. These cells originate from CD45RA+ naive cells within the CD4+CD25^high T-cell compartment. In particular, this subpopulation homogeneously expresses FOXP3, CD62L, CCR7, cytotoxic T lymphocyte–associated antigen-4, and maintains robust suppressive activity after expansion. In contrast, cell lines derived from CD45RA^– memory-type CD4+CD25^high T cells show only moderate suppression and do not maintain FOXP3 expression.⁵

Although the CD4+CD25^high Treg compartment in adult peripheral blood comprehends naive as well as memory cells, only the naive CD45RA+ subpopulation gives rise to homogeneous Treg cell lines, since memory-type Treg cells (CD45RA–) could downregulate FOXP3 expression and lose their suppressive activity.⁵ For this reason, we agree with Bates et al¹ that FOXP3-positive Treg cells represent an important therapeutic target for breast cancer.

AUTHOR'S 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. Petersen RP, Campa MJ, Sperlazza J, et al: Tumor infiltrating Foxp3(+) regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer 107:2866-2872, 2006[CrossRef][Medline]

3. Hiraoka N, Onozato K, Kosuge T, et al: Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12:5423-5434, 2006[Abstract/Free Full Text]

4. Yamaguchi T, Sakaguchi S: Regulatory T cells in immune surveillance and treatment of cancer. Semin Cancer Biol 16:115-123, 2006[CrossRef][Medline]

5. 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]

Related Reply

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  Gaynor J. Bates and Alison H. Banham
  JCO 2007 25: 30 [Full Text]

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