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Originally published as JCO Early Release 10.1200/JCO.2008.20.0675 on March 2 2009 © 2009 American Society of Clinical Oncology.
FOXP3 Expression and Prognosis: Role of Both the Tumor and T CellsCenter for Translational Medicine in Women's Health, University of Washington, Seattle, WA FOXP3 is a transcription factor that is well known to be the hallmark of immune suppressive T regulatory cells (Tregs), especially thymically derived natural Tregs.1 Lack of FOXP3-expressing T cells can lead to autoimmune disease, whereas an abundance of FOXP3-expressing T cells can result in immune deficiency. Increased levels of FOXP3-positive Tregs in peripheral blood and tumor have been reported in patients with various types of cancer, including ovarian,2,3 breast,4 and other tumors.5 Abundance of FOXP3-positive Tregs in tumors has been associated with worse prognosis.2–4 For example, Bates et al4 reported that high numbers of FOXP3-positive Tregs were identified in patients with ductal carcinoma in situ at increased risk of relapse, and in patients with invasive breast tumors with both shorter relapse-free and overall survival. In addition to their potential value in predicting disease progression and relapse, FOXP3-positive Tregs have recently been reported to be a marker for monitoring therapeutic response. A recent study has suggested that pathologic complete response of breast carcinoma to neoadjuvant chemotherapy is associated with the disappearance of tumor-infiltrating FOXP3-positive Tregs.6 Furthermore, FOXP3 has been studied as a therapeutic target, and it has been shown that vaccination to eradicate FOXP3-expressing cells enhances tumor immunity.7 It had been assumed that Tregs were the major cell type mediating immune suppression regulated by FOXP3 expression. Only recently has it been demonstrated that the tumor cell itself can express FOXP3. In this issue of Journal of Clinical Oncology, Merlo et al8 suggest that FOXP3 is expressed in breast cancer cells, and the expression level is associated with patient survival. Using immunohistochemical staining, the investigators characterized FOXP3 expression in 397 primary breast carcinoma specimens from two clinical trials. FOXP3 stained positive in the majority of the breast cancer tissues examined (57% and 73% in the Milan 3 and 1 trials, respectively). Both cytoplasmic and nuclear staining of FOXP3 was observed. Additional analysis revealed that FOXP3 expression in tumors was associated with worse overall survival, and the risk increased with increasing FOXP3 immunostaining intensity. Whether FOXP3 expression in tumor cells affects endogenous tumor-specific immunity is not known. However, the finding that FOXP3 is expressed in tumor cells implies that T-cell function may be modulated not only by FOXP3 in Tregs but also by tumor-associated FOXP3. The expression of FOXP3 in tumor cells has also been recently reported in pancreatic cancer,9 melanoma,10 and other tumor cell lines.11 Hinz et al9 reported that FOXP3 is expressed in pancreatic cancer cells, and the FOXP3-expressing cancer cells inhibited the proliferation of CD4+CD25– T cells, potentially contributing to immune evasion of the tumor cells. Ebert et al10 reported the expression of FOXP3 in not only Tregs but also melanoma cells in metastatic melanoma tissue and multiple tumor cell lines derived from melanoma and other solid tumors. Whether FOXP3 is also expressed by tumor-infiltrating Tregs is not addressed in the current article. Future studies in this area should be performed to investigate whether the FOXP3 expression in tumor cells and expression in Tregs are related, and assess which is more closely associated with prognosis. It should also be recognized that FOXP3 expressed in tumors may be a different transcript than FOXP3 expressed in Tregs.10 A FOXP3 mRNA variant lacking exons 3 and 4 has been identified in tumor cell lines but not in CD4+FOXP3+ T cells.10 The question that remains is the mechanism by which expression of FOXP3 in tumor cells affects prognosis. Hinz et al9 suggested that inhibition of an effector T-cell response may contribute to immune evasion. As reported in the current article, Merlo et al8 found that FOXP3 expression was associated with overall and distant metastasis-free survival but not with local relapse; therefore, the authors suggest that FOXP3 expression might be related to the metastatic potential of the tumor rather than to suppression of a specific immune response. The hypothesis that FOXP3 expressed in cancer cells might modulate expression of chemokine receptors and other genes, and thus influence invasion and metastasis, remains to be tested. Paradoxically, another group studying the expression of FOXP3 in breast cancer reported that FOXP3 is an X-linked breast cancer suppressor gene and a novel transcriptional repressor for the breast cancer oncogene SKP2, and suppresses breast tumor cell growth.12,13 The apparent discrepancy between these results remains to be investigated in future studies. Nevertheless, the finding that FOXP3 can be expressed by not only tumor-infiltrating Tregs but also tumor cells has two important implications. First, caution needs to be taken when interpreting gene expression data on FOXP3 expression in tumors. Increased levels of FOXP3 mRNA expression may be a result of not only an increased influx of Tregs but also the increased expression of FOXP3 directly in tumor cells. This understanding has significant importance for developing assays on the basis of FOXP3 for prognosis or drug monitoring. Second, we need to recognize that FOXP3-targeted therapy may need to be targeted at not only Tregs but also FOXP3-positive tumor cells, although the role of FOXP3 in regulating tumor cell growth remains to be clarified. The expression of FOXP3 in tumor cells indicates that FOXP3-targeted drugs must to be able to penetrate into the tumor bed, which is much more challenging than depleting FOXP3 in the periphery. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061, 2003. 2. Curiel TJ, Coukos G, Zou L, et al: Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949, 2004.[CrossRef][Medline] 3. Leffers N, Gooden MJ, de Jong RA, et al: Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother epub ahead of print on September 13, 2008. 4. 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. 5. Zou W: Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6:295–307, 2006.[CrossRef][Medline] 6. Ladoire S, Arnould L, Apetoh L, et al: Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells. Clin Cancer Res 14:2413–2420, 2008. 7. Nair S, Boczkowski D, Fassnacht M, et al: Vaccination against the forkhead family transcription factor Foxp3 enhances tumor immunity. Cancer Res 67:371–380, 2007. 8. Merlo A, Casalini P, Carcangiu ML, et al: FOXP3 expression and overall survival in breast cancer. J Clin Oncol 27:1746–1752, 2009. 9. Hinz S, Pagerols-Raluy L, Oberg HH, et al: Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res 67:8344–8350, 2007. 10. Ebert LM, Tan BS, Browning J, et al: The regulatory T cell-associated transcription factor FoxP3 is expressed by tumor cells. Cancer Res 68:3001–3009, 2008. 11. Karanikas V, Speletas M, Zamanakou M, et al: Foxp3 expression in human cancer cells. J Transl Med 6:19; 2008.[CrossRef][Medline] 12. Zuo T, Wang L, Morrison C, et al: FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell 129:1275–1286, 2007.[CrossRef][Medline] 13. Zuo T, Liu R, Zhang H, et al: FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2. J Clin Invest 117:3765–3773, 2007.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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