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Originally published as JCO Early Release 10.1200/JCO.2009.23.2439 on May 26 2009 © 2009 American Society of Clinical Oncology.
Reply to C. Badoual et alSchool of Surgery, University of Western Australia, Nedlands, Australia
School of Surgery, University of Western Australia, Nedlands; and Colorectal Cancer Unit, St John of God Hospital, Subiaco, Australia
School of Surgery, University of Western Australia, Nedlands, Australia We thank Badoual et al1 for their correspondence regarding our study,2 in which we found that a high density of intratumoral FOXP3+ regulatory T cells (Tregs) in colorectal cancer (CRC) was associated with good prognosis. Although our findings were in contrast with observations published for several other solid tumor types,3–5 Badoual et al argued that our results should not have been entirely unexpected in light of previous results obtained in animal models of colon cancer6,7 and in human lymphomas8 and head and neck cancers.9 They also proposed some appealing explanations of why Tregs may be linked to better survival, including direct antitumor effects, thus providing a stimulus for additional investigation in this field. Two preclinical studies6,7 in which the adoptive transfer of Tregs in mouse models was shown to prevent the formation of adenomas and cause regression of established tumors were cited by Badoual et al1 as being supportive of our findings.2 However, we evaluated Treg densities in tumor and adjacent normal mucosal tissues and have no data on how these parameters relate to the level of circulating Tregs. Clearly, this would be an interesting area for additional study, particularly in relation to possible changes in blood and tissue Tregs caused by cytotoxic chemotherapy and whether this affects the antitumor immune response. The contrasting prognostic associations observed in our study for Tregs localized within tumor and adjacent normal tissue highlight the need for investigation of both compartments, perhaps also in conjunction with the level of circulating Tregs. A different prognostic role for Tregs according to tumor stage was one explanation put forward by Badoual et al1 to explain contradictory results in the literature. Although our study2 did not examine metastatic CRC cases, we found that high Treg density was associated with better survival in both stage II and stage III CRC. Second, CD8+ to FOXP3+ and CD45RO+ to FOXP3+ ratios were examined for prognostic significance but found to be inferior to FOXP3+ cell density alone. However, we agree that information on the relationship between FOXP3+ cell density and the expression of effector molecules such as granzyme and perforin would be useful; indeed, this is currently being investigated by our group. As discussed by Badoual et al, functional studies on tumor-infiltrating FOXP3+ cells are required to help explain the biologic basis for their association with prognosis in CRC and in other cancer types. Regardless of why the density of tumor-infiltrating Tregs appears to have different prognostic value for different cancer types, the fact remains that it was a strong and independent marker in our study2 of CRC. Confirmation of our findings by independent studies could lead to the routine use of Treg density, in combination with vascular and serosal invasion, for the improved prognostic stratification of stage II CRC. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENT P.S. is supported by a Russell Walter Gibbon Postgraduate Research Award from the University of Western Australia and by a grant from the Colorectal Surgical Society of Australia and New Zealand Foundation. REFERENCES
1. Badoual C, Hans S, Fridman WH, et al: Revisiting the prognostic value of regulatory T cells in patients with cancer. J Clin Oncol 27:e5–e6, 2009. 2. Salama P, Phillips M, Grieu F, et al: Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192, 2009. 3. 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] 4. 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. 5. Gao Q, Qiu SJ, Fan J, et al: Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593, 2007. 6. Erdman SE, Sohn JJ, Rao VP, et al: CD4+CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+ mice. Cancer Res 65:3998–4004, 2005. 7. Erdman SE, Poutahidis T, Tomczak M, et al: CD4+CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice. Am J Pathol 162:691–702, 2003. 8. Alvaro T, Lejeune M, Salvadó MT, et al: Outcome in Hodgkin's lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 15:1467–1473, 2005. 9. Badoual C, Hans S, Rodriguez J, et al: Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12:465–472, 2006.
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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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