Interleukin 2-mediated conversion of ovarian cancer-associated CD4+ regulatory T cells into proinflammatory interleukin 17-producing helper T cells.
Epithelial ovarian cancer (EOC) is a highly inflammatory malignancy, characterized by the presence, at the tumor site, of regulatory T cells (Treg) that suppress antitumor immunity. Recently, a new lineage of CD4+ T cells producing the proinflammatory cytokine interleukin (IL)-17 [T helper (TH) 17] has been identified as a major player in some autoimmune diseases. The role of TH17 cells in cancer, however, and their relationship with coexisting Treg populations, whose differentiation is partially controlled by the same mediators (ie, transforming growth factor-beta), are yet unclear. Here, we show that EOC-associated/infiltrating lymphocytes derived by culturing tumor samples in the presence of IL-2 contain significant frequencies of TH17 cells, coproducing interferon-gamma (IFN)-gamma and tumor necrosis factor (TNF)-alpha, which represent, in some cases, up to 40% of total CD4+ T cells. TH17 cells were also detected ex vivo, but at lower proportions than in cultured tumor-infiltrating lymphocytes/tumor-associated lymphocytes, and were confined to the CD4+CD25- fraction. Remarkably, analysis of EOC-associated conventional CD4CD25 T cell and Treg populations isolated ex vivo from tumor samples by cell sorting and cultured with tumor-associated CD3- cells in the presence of IL-2 revealed that EOC Treg stimulated under these conditions were rapidly converted into TH17 cells, down-regulated FOXP3 expression, and lost their suppressive capacity. Thus, although the impact of TH17 cells on the evolution of EOC remains to be established, our data suggest that local IL-2 treatment in ovarian cancer may result in the conversion of tumor-associated Treg into TH17 cells, relieve Treg-mediated suppression, and contribute to enhance antitumor immunity.
Leveque
Lucie
L
Institut National de la Santé et de la Recherche Médicale, CLCC René Gauducheau, Saint Herblain section signFaculty of Medicine, University of Nantes, Nantes, France.
Deknuydt
Florence
F
Bioley
Gilles
G
Old
Lloyd J
LJ
Matsuzaki
Junko
J
Odunsi
Kunle
K
Ayyoub
Maha
M
Valmori
Danila
D
D002277:Carcinoma / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology; D010051:Ovarian Neoplasms / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma