Cellsand Inhibit the Function of Infiltrating T Human Metastatic Melanoma Lymph Nodes Regulatory T Cells Are Overrepresented in high CD25+ Foxp3 Expressing CD4

Dominant tolerance is mediated by regulatory T cells (T reg ) that control harmful autoimmune T cells in the periphery. In this study, we investigate the implication of T reg in modulating infiltrating T lymphocytes in human metastatic melanoma. We found that CD4 (cid:1) CD25 high 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 (cid:2) chain repertoire. They inhibit in vitro the proliferation and cytokine production of infiltrating CD4 (cid:1) CD25 (cid:3) and CD8 (cid:1) T cells (IL-2, IFN- (cid:4) ) through a cell-contact-dependent mechanism, thus behaving as T reg . In some cases, the presence of T reg type 1/Th3-like lymphocytes could also be demonstrated. Thus, T reg 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 T reg to reinforce local antitumor immune responses. The Journal of Immunology, 2004, 173: 1444–1453.

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