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* Unité de Biologie Moléculaire du Gène, Institut National de la Santé et de la Recherche Médicale (INSERM) U277, Institut Pasteur,
Department of Dermatology and INSERM U532, Skin Research Institute, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris,
Department of Pathology, Hôpital Saint-Louis, and
Immunology A, Centre d’Étude et de la Recherche en Virologie et en Immunologie, Institut National de Science et Recherche Medicale, Unité 543, Hôpital Pitié-Salpetrière, Paris, France
Dominant tolerance is mediated by regulatory T cells (Treg) that control harmful autoimmune T cells in the periphery. In this study, we investigate the implication of Treg in modulating infiltrating T lymphocytes in human metastatic melanoma. We found that CD4+CD25high T cells are overrepresented in metastatic lymph nodes (LNs) with a 2-fold increased frequency compared with both tumor-free LNs and autologous PBMCs. These cells express the Foxp3 transcription factor, display an activated phenotype, and display a polyclonal TCR V
chain repertoire. They inhibit in vitro the proliferation and cytokine production of infiltrating CD4+CD25– and CD8+ T cells (IL-2, IFN-
) through a cell-contact-dependent mechanism, thus behaving as Treg. In some cases, the presence of Treg type 1/Th3-like lymphocytes could also be demonstrated. Thus, Treg are a major component of the immunosuppressive microenvironment of metastatic melanoma LNs. This could explain the poor clinical response of cancer patients under immunotherapeutic protocols, and provides a new basis for future immunotherapeutic strategies counteracting in vivo Treg to reinforce local antitumor immune responses.
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