Research Papers:

Elevated level of Interleukin-35 in colorectal cancer induces conversion of T cells into iTr35 by activating STAT1/STAT3

Yanhui Ma, Lei Chen, Guohua Xie, Yunlan Zhou, Chaoyan Yue, Xiangliang Yuan, Yingxia Zheng, Weiwei Wang, Lin Deng and Lisong Shen _

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Oncotarget. 2016; 7:73003-73015. https://doi.org/10.18632/oncotarget.12193

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Yanhui Ma1,*, Lei Chen2,*, Guohua Xie1, Yunlan Zhou1, Chaoyan Yue1, Xiangliang Yuan1, Yingxia Zheng1, Weiwei Wang1, Lin Deng1, Lisong Shen1

1Department of Laboratory Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China

2Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China

*These authors contributed equally to this work

Correspondence to:

Lisong Shen, email: [email protected]

Keywords: interleukin-35, colorectal cancer, STAT1, STAT3

Received: January 11, 2016     Accepted: September 12, 2016     Published: September 22, 2016


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.

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