Targeting cytokines secreted by CD4+ CD25high CD127low regulatory T cells inhibits ovarian cancer progression.

Abstract

Epithelial ovarian cancer (EOC) is one of the major malignant cancers with high rates of early metastasis in which regulatory T cells (Tregs) play an important role. Tregs suppress immune responses and promote the development of tumours in patients withEOC. However, the underlying mechanisms remain unclear. In this study, we found higher levels of CD4+ CD25high CD127low Tregs inpatients with EOC than in patients with benign ovarian tumours and healthy donors. The immune inhibitory effect of Tregs functions by maintaining high levels of immunosuppressive cytokines in EOC. The high levels of Tregs and related cytokines (TGF-β1 or IL-10) were associated with lymphatic metastasis and FIGO stages of patients with EOC. Expression of matrix metalloproteinase (MMP)-2 and tissue inhibitors of metalloproteinase (TIMP)-2 in EOC cell lines were significantly regulated in the coculture experiment with CD4+ CD25high CD127low Tregs sorted from EOC patients. Levels of MMP-2 and TIMP-2 conversely changed after blocking IL-10R and TGF-β1R in EOC cells. The invasion ability of EOC cells was also significantly downregulated in this process. The metastasis of EOC cells was correlated with the levels of TGF-β1 or IL-10. These findings suggested that immunosuppressive cytokines secreted by CD4+ Tregs could be a novel target for inhibiting EOC progression.