Interleukin 2-mediated Conversion of Ovarian Cancer-associated CD4⁺ Regulatory T Cells Into Proinflammatory Interleukin 17-producing Helper T Cells

Abstract

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 the proinflammatory cytokine interleukin (IL)-17 [T helper (T_H) 17] has been identified as a major player in some autoimmune diseases. The role of T_H17 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-β), 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_H17 cells, coproducing interferon-γ (IFN)-γ and tumor necrosis factor (TNF)-α, which represent, in some cases, up to 40% of total CD4⁺ T cells. T_H17 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_H17 cells, down-regulated FOXP3 expression, and lost their suppressive capacity. Thus, although the impact of T_H17 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_H17 cells, relieve T_reg-mediated suppression, and contribute to enhance antitumor immunity.