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*Skin Cancer Unit, German Cancer Research Center and University Hospital Mannheim, Heidelberg, Germany;
Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany;
Immunomonitoring Unit, National Center for Tumor Diseases and Institute for Immunology, Heidelberg, Germany; and
Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi, Japan
CD4+CD25+Foxp3+ regulatory T cells (Treg) known to mediate self-tolerance were also shown to contribute to tumor progression. In mouse melanoma transplantation models, Treg depletion resulted in the stimulation of antitumor immune responses and tumor eradication. To study Treg in conditions close to the clinical situation, we used a ret transgenic mouse spontaneous melanoma model, which, in contrast to transplantation models, resembles human melanoma regarding clinical development. Significantly higher numbers of Treg were found in skin tumors and metastatic lymph nodes at early stages of melanoma progression compared with more advanced stages accompanied by the elevated CCR4 expression on Treg and higher production of its ligand CCL2 in tumor lesions. Numbers of tumor infiltrating Treg inversely correlated with Treg amounts in the bone marrow, suggesting their possible recruitment to melanoma lesions from this organ. The immunosuppressive function of Treg from transgenic tumor-bearing mice was similar to that from transgenic tumor-free mice or nontransgenic littermates. Although anti-CD25 mAb injections resulted in the efficient Treg depletion from lymphoid organs of transgenic mice, melanoma development was not significantly delayed. Furthermore, the treatment of mice with macroscopical tumors also failed to inhibit tumor progression, which correlated with the inability to deplete intratumoral Treg. We suggest that in the autochthonous melanoma genesis, other immunosuppressive cells could play an important role and replace immunosuppressive, tumor-promoting functions of Treg. Therefore, effective melanoma immunotherapy should include the inhibition of Treg migration into the tumor combined with neutralization of other immunosuppressive cells and factors in the tumor microenvironment.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Dr. Mildred Scheel Foundation for Cancer Research (Grant 106096 to V.U. and D.S.), the Initiative and Networking Funds of the Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer (to V.U., D.S. and K.M.), and by the Framework Program of the European Union (Grant Cancer Immunotherapy 518234 to D.S. and W.O.).
2 Current address: Department of Dermatology, University Hospital Essen, 45122 Essen, Germany.
3 Address correspondence and reprint requests to Dr. Viktor Umansky, Skin Cancer Unit, German Cancer Research Center and University Hospital Mannheim, 69120 Heidelberg, Germany. E-mail address: v.umansky{at}dkfz.de
4 Abbreviations used in this paper: Treg, regulatory T cell; LN, lymph node; BM, bone marrow; Tcon, conventional T cell.
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