Targeting cytokines secreted by CD4⁺CD25^highCD127^low 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 with EOC. However, the underlying mechanisms remain unclear. In this study, we found higher levels of CD4+CD25highCD127low Tregs in patients 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+CD25highCD127low 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.

Presence of regulatory T-cells in endometrial cancer predicts poorer overall survival and promotes progression of tumor cells

“…Furthermore, they can also be detected in the tumor microenvironment (TME). In various cancer entities, a high number of Treg has been reported to be associated with a worse prognosis by suppressing antitumor responses [32][33][34] in, for example epithelial ovarian cancer [35,36] and non-small-cell lung cancer [37]. It is well known, that the Treg marker FoxP3 can be upregulated or downregulated depending on the human cancer type [26,38].…”

“…The proliferation rate of Treg seemed to be even more increased when the tumor cells expressed Human Leucocyte Antigen G [ 47 ] or by transforming growth factor-ß1 [ 48 ]. In summary, these data indicate that induced Treg are immunosuppressive and promote tumor progression [ 35 ].…”

The complex role of IL-10 in malignant ascites: a review

“…[ 92 ] Beyond OC cells, IL-10 has been found in several human carcinoma cell lines and cells isolated directly from tumor tissues, with pancreatic cancer cell-derived IL-10 suppressing CTL lytic function of T cells [ 93 – 95 ]. The metastatic ability of EOC cells correlates with IL-10 and TGF-β in ascites, associated with altered MMP-2 and TIMP-2 levels [ 96 ] (Fig. 1 ).…”

New Achievements from Molecular Biology and Treatment Options for Refractory/Relapsed Ovarian Cancer—A Systematic Review

“…CD24 might be a potential target as well, but data are outstanding [7]. The correlation of EOC cell metastasis with the levels of TGF-β1 or IL-10 suggested that immunosuppressive cytokines could be a novel target for inhibiting EOC progression [81].…”