Abstract
IL-35 is a novel heterodimeric and inhibitory cytokine, composed of interleukin-12 subunit alpha (P35) and Epstein-Barr virus -induced gene 3 (EBI3). IL-35 has been reported to be produced by a range of cell types, especially regulatory T cells, and to exert immunosuppressive effects via the STATx signaling pathway. In this study, we demonstrated that IL-35 expression was elevated in both serum and tumors in patients with colorectal cancer. IL-35 mainly expressed in CD4+ T cells in human colorectal cancer tumors and adjacent tissues. Increased IL-35 expression in tumor-adjacent tissues was significantly associated with tumor metastasis. IL-35 inhibited the proliferation of CD4+CD25− T effector cells in vitro in a dose-dependent manner, and its suppression was partially reversed by applying IL-35-neutralizing antibodies. IL-35 treatment activated the phosphorylation of both STAT1 and STAT3 in human CD4+ T cells. Meanwhile, IL-35 induced a positive feedback loop to promote its own production. We observed that Tregs obtained from colorectal cancer patients were capable of inducing more IL-35 production. In addition, EBI3 promoter-driven luciferase activity was higher than that of the mock plasmid after IL-35stimulation. Thus, our study indicates that the high level of IL-35 in colorectal cancer promotes the production of IL-35 via STAT1 and STAT3, which suppresses T cell proliferation and may participate in tumor immunotolerance.
Highlights
Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide [1,2,3]
CD25−CD4+ We found that IL-35 enhanced Epstein-Barr virus -induced gene 3 (EBI3) mRNA expression and IL-35 protein levels in T cells and a decrease in Tconv proliferation, suggesting that they were induced to differentiate into iTr35 cells
To determine whether Treg cells and IL-35 are involved in the development of CRC, we first measured the number of circulating Treg cells in PBL using flow cytometry
Summary
Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide [1,2,3]. Some studies have indicated that an increased number of regulatory T cells in the blood and tumors of colorectal cancer patients may result in an immune-compromised state against cancer. These studies suggest that strategies to overcome regulatory T cell activity may be beneficial in treatments for human colorectal cancer [7,8,9]. A mathematical model was used www.impactjournals.com/oncotarget to show that IL-35 promoted tumorigenesis in colorectal cancer [16] Because these results were based on a computer analysis, laboratory-based evidence for the role of IL-35 and/or iTr35 in cancer was needed to support their relationship and functions in humans
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