Liraglutide activates nature killer cell-mediated antitumor responses by inhibiting IL-6/STAT3 signaling in hepatocellular carcinoma

Xian Lu; Chun Xu; Jie Dong; Shuguang Zuo; Hailin Zhang; Chunping Jiang; Junhua Wu; Jiwu Wei

doi:10.1016/j.tranon.2020.100872

Liraglutide activates nature killer cell-mediated antitumor responses by inhibiting IL-6/STAT3 signaling in hepatocellular carcinoma

Transl Oncol. 2021 Jan;14(1):100872. doi: 10.1016/j.tranon.2020.100872. Epub 2020 Sep 23.

Authors

Xian Lu¹, Chun Xu², Jie Dong³, Shuguang Zuo³, Hailin Zhang³, Chunping Jiang⁴, Junhua Wu⁵, Jiwu Wei⁶

Affiliations

¹ Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China; Kunshan Hospital of Traditional Chinese Medicine, Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine, Suzhou 215300, China.
² Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China; Department of Pathology, School of Medicine, Southeast University, Nanjing 210009, China.
³ Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China.
⁴ Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China; The Affiliated Drum Hospital, Medical School of Nanjing University, Nanjing 210093, China.
⁵ Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China. Electronic address: [email protected].
⁶ Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China. Electronic address: [email protected].

Abstract

Inflammatory IL-6/STAT3 signaling is constitutively activated in diverse cancers and is associated with malignant cell proliferation, invasion and escape of antitumor immunosurveillance. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is commonly used to treat insulin-resistant diabetes. In this study, for the first time, we showed that liraglutide remarkably improved the antitumor immune responses in hepatocellular carcinoma (HCC). Furthermore, we showed that the antitumor activity was mediated by nature killer cells (NKs) but not CD8⁺ T cells. Finally, we showed that liraglutide enhanced NK-mediated cytotoxicity by suppressing the IL-6/STAT3 signaling pathway in HCC cells. Our findings unveil a novel therapeutic role of liraglutide by manipulating the innate immunity in cancer therapy.