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Originally published as JCO Early Release 10.1200/JCO.2009.23.0680 on May 26 2009 © 2009 American Society of Clinical Oncology.
Revisiting the Prognostic Value of Regulatory T Cells in Patients With CancerFaculté de Médecine, Immunothérapie des Cancers (EA 4054), Université Paris Descartes; Ecole Nationale Vétérinaire d'Alfort; and Service d'Anatomie Pathologique, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
Department of Otorhinolaryngology–Head and Neck Surgery, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
Service d'Immunologie Biologique, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
Department of Otorhinolaryngology–Head and Neck Surgery, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA
Faculté de Médecine, Immunothérapie des Cancers, Université Paris Descartes; Ecole Nationale Vétérinaire d'Alfort; and Service d'Immunologie Biologique, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France To the Editor: In a recent issue of Journal of Clinical Oncology, Salama et al1 reported better survival associated with a high density of intratumoral FOXP3+ regulatory T cells (Tregs) in colorectal cancer. In their discussion, the authors stated that these results were unexpected, surprising, and in marked contrast to the poor prognostic value of Treg presence in other tumors.2–4 However, it must be emphasized that these results are in line with the preclinical studies of Erdman et al5 performed in apcMin/+ mice, in which the tumor suppressor gene apc was inactivated, leading to formation of intestinal adenomas and recapitulating early events in human colorectal cancer. Adoptive transfer of Tregs into these mice resulted in prevention of intestinal adenomas and regression of established tumors. In another mouse model of bacteria-driven inflammation and cancer in the lower bowel, administration of Tregs also inhibited microbially induced inflammation and development of cancer.6 In patients with follicular lymphoma and Hodgkin's lymphoma, it is now well established that high number of intratumoral Tregs is associated with longer disease-free and overall survival, even in multivariate analyses.7–9 This correlation between the number of Tregs and favorable clinical outcome has also recently been extended in some solid tumors. In patients with head and neck cancer, we found that tumor infiltration by FOXP3+CD4+ Tregs was positively associated with better locoregional control of the tumor.10 In our study, multivariate analysis showed that the only significant prognostic factors related to locoregional control were T stage and Treg infiltration of the tumor. Frequency of FOXP3+CD4+ Tregs has also been shown to be higher in patients with no evidence of disease after oncologic therapy than in patients with active disease.11 Various parameters may explain these seemingly contradictory results regarding prognostic value of Tregs in patients with cancer. First, the role of Tregs seems to differ according to tumor stage. For example, patients with early-stage (stage I) non–small-cell lung carcinoma and a high proportion of Tregs relative to tumor-infiltrating lymphocytes had a significantly high risk of recurrence.12 In the whole population of patients with ovarian cancer, Tregs were associated with poor prognosis,2 whereas in patients with advanced or metastatic disease, absolute number of FOXP3+ lymphocytes infiltrating tumor epithelium was an independent factor for longer disease-specific survival.13 These data are supported by a preclinical study in mice, in which Tregs often served as the dominant immune escape mechanism early in tumor progression; the elimination of these cells before tumor challenge resulted in tumor-free survival in most mice, whereas their depletion in mice with established tumors had no therapeutic effect.14 Second, because it is supposed that the deleterious effect of Tregs is mediated by their inhibitory activity on antitumor effector cells, it is not surprising that various studies have reported that the ratio of CD8+ T cells to Tregs had more impact on patient survival that the number of Tregs or intraepithelial CD8+ T cells alone.15,16 Focusing only on Tregs—without knowledge of the balance between Tregs and effector cells—may lead to some bias in data interpretation. Third, unlike in mice, FOXP3 expression, which has been used in studies by Salama et al1 and others to define Tregs, is not confined to certain populations in humans. It has been shown that activated CD4+CD25– effector T cells transiently express FOXP3 with or without acquisition of suppressive functions.17,18 Subsets of CD8+ T cells as well as tumor cells might also express FOXP3.19 Therefore, although FOXP3 is currently the best marker available for immunohistochemical staining to characterize Tregs, the simple use of this marker may overestimate this Treg population. Depending on the study and proportion of FOXP3+-activated CD4+ T cells or CD8+ T cells in tissue specimens, the simple enumeration of FOXP3+-positive cells without functional analysis will not correspond to the same levels of Tregs in the various samples and thus may lead to bias in interpretation of data. With respect to mechanisms underlying the favorable role of Tregs in tumor control, two hypotheses could be proposed. Hematologic malignancies and solid tumors (head and neck cancer and colon cancer), in which presence of Tregs correlates with good clinical outcome, are tumors heavily infiltrated by inflammatory innate immune cells (ie, macrophages and neutrophils), producing inflammatory cytokines, growth factors, and pro-angiogenic molecules favoring tumor progression.20,21 In mice, Tregs have the ability to suppress inflammation triggered by innate immune cells.22 In humans, FasL+ Tregs may kill monocytes and macrophages and then decrease their protumor effect during cancer development.23 In addition, it has been well documented that Tregs may express cytotoxic molecules such as granzyme and perforin and induce cell death of normal cells such as B cells.24 It has been demonstrated that adoptive immunotherapy with CD4+CD25+ Tregs can also decrease tumor multiplicity through rapid induction of apoptosis of intestinal tumors, which supports the possibility of Tregs directly or indirectly inducing tumor apoptosis.5 We feel that our comments will help to better highlight the work of Salama et al.1 Finally, we hope our comments show that the data presented by Salama et al were original, but not so unexpected. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENT Supported by European Economic Community Grant No. LSH-2005-518234 in cancer immunotherapy; Comite du Val de Marne, Ligue Nationale Contre le Cancer; Immucan Project, Pöle de Compétitivité Medicen; Cancéropôle d'Île-de-France; Institut National du Cancer; Clinical Investigation Center for Biotherapies, Assistance Publique Hôpitaux de Paris, and National Institutes of Health Grant R01CA108854. REFERENCES
1. 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. 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. 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. 4. Kobayashi N, Hiraoka N, Yamagami W, et al: FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res 13:902–911, 2007. 5. 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. 6. 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. 7. Lee AM, Clear AJ, Calaminici M, et al: Number of CD4+ cells and location of forkhead box protein P3-positive cells in diagnostic follicular lymphoma tissue microarrays correlates with outcome. J Clin Oncol 24:5052–5059, 2006. 8. Alvaro T, Lejeune M, Salvado MT, et al: Outcome in Hodgkin's lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 11:1467–1473, 2005. 9. Carreras J, Lopez-Guillermo A, Fox BC, et al: High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood 108:2957–2964, 2006. 10. 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. 11. Strauss L, Bergmann C, Gooding W, et al: 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 13:6301–6311, 2007. 12. 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] 13. 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 58:449–459, 2009.[CrossRef][Medline] 14. Elpek KG, Lacelle C, Singh NP, et al: CD4+CD25+ T regulatory cells dominate multiple immune evasion mechanisms in early but not late phases of tumor development in a B cell lymphoma model. J Immunol 178:6840–6848, 2007. 15. Sato E, Olson SH, Ahn J, et al: Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 102:18538–18543, 2005. 16. 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. 17. Walker MR, Kasprowicz DJ, Gersuk VH, et al: Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25– T cells. J Clin Invest 112:1437–1443, 2003.[CrossRef][Medline] 18. 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] 19. Cosmi L, Liotta F, Lazzeri E, et al: Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes. Blood 102:4107–4114, 2003. 20. Badoual C, Bouchaud G, Agueznay Nel H, et al: The soluble alpha chain of interleukin-15 receptor: A proinflammatory molecule associated with tumor progression in head and neck cancer. Cancer Res 68:3907–3914, 2008. 21. Schottelius AJ, Dinter H: Cytokines, NF-kappaB, microenvironment, intestinal inflammation and cancer. Cancer Treat Res 130:67–87, 2006.[Medline] 22. Maloy KJ, Salaun L, Cahill R, et al: CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med 197:111–119, 2003. 23. Venet F, Pachot A, Debard AL, et al: Human CD4+CD25+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J Immunol 177:6540–6547, 2006. 24. Grossman WJ, Verbsky JW, Barchet W, et al: Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21:589–601, 2004.[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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