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 (T-reg) that suppress antitumor immunity. Recently, a new lineage of CD4(+) T cells producing inflammatory cytokine interleukin (IL)-17 [T helper (T-H) 17] has been identified as a major player in some autoimmune diseases. The role of T(H)17 cells in cancer, however, and their relationship with coexisting T-reg 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 T(H)17 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. T(H)17 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 CD4(+)CD25(-) T cell and T-reg 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 T-reg stimulated under these conditions were rapidly converted into T(H)17 cells, down-regulated FOXP3 expression, and lost their suppressive capacity, Thus, although the impact of T(H)17 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 T-reg into T(H)17 cells, relieve T-reg-mediated suppression, and contribute to enhance antitumor immunity.