Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells.
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(+)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 Vbeta chain repertoire. They inhibit in vitro the proliferation and cytokine production of infiltrating CD4(+)CD25(-) and CD8(+) T cells (IL-2, IFN-gamma) 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.
Viguier
Manuelle
M
Unité de Biologie Moléculaire du Gène, Institut National de la Santé et de la Recherche Médicale (INSERM) U277, Institut Pasteur, Paris, France.
Lemaître
Fabrice
F
Verola
Olivier
O
Cho
Min-Sun
MS
Gorochov
Guy
G
Dubertret
Louis
L
Bachelez
Hervé
H
Kourilsky
Philippe
P
Ferradini
Laurent
L
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008207:Lymphatic Metastasis; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016207:Cytokines; D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016212:Transforming Growth Factor beta; D016753:Interleukin-10