Tumor cell-intrinsic Tim-3 promotes liver cancer via NF-κB/IL-6/STAT3 axis

• Published in: Oncogene Vol. 37; no. 18; pp. 2456 - 2468
• Main Authors: Zhang, Hualin, Song, Yang, Yang, Huimin, Liu, Zhiyan, Gao, Lifen, Liang, Xiaohong, Ma, Chunhong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2018; Nature Publishing Group
• Subjects: 13/1; 13/105; 13/109; 13/31; 13/51; 13/89; 14/105; 14/19; 38/1; 38/89; 631/67/1059/602; 631/67/1504/1610; Adolescent; Adult; Aged; Animals; Antibodies, Monoclonal - therapeutic use; Apoptosis; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Cell Biology; Cell Transformation, Neoplastic - genetics; Cells, Cultured; Female; Hep G2 Cells; Hepatitis A Virus Cellular Receptor 2 - genetics; Hepatitis A Virus Cellular Receptor 2 - immunology; Hepatitis A Virus Cellular Receptor 2 - physiology; Hepatocytes; Human Genetics; Humans; Interleukin 6; Interleukin-6 - metabolism; Internal Medicine; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver Neoplasms - therapy; Lymphocytes T; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Mucin; NF-kappa B - metabolism; NF-κB protein; Oncology; Phosphorylation; RNA-mediated interference; Rodents; Signal Transduction - genetics; Stat3 protein; STAT3 Transcription Factor - metabolism; Tumor cells; Tumorigenesis; Young Adult
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0140-4

T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), mediating immune exhaustion in tumor microenvironment, has become a promising target for tumor therapy. However, the exact mechanisms for tumor cell-intrinsic Tim-3 in tumor development and its potential contribution in Tim-3-targeted therapy strategy have not been elucidated yet. In this study, we showed that human liver cancer tissues contained high ratio of Tim-3-expressing hepatocytes, and cytokines rich in tumor microenvironment and HBV involved in Tim-3 upregulation in malignant hepatocytes. We demonstrated that hepatocyte-specific Tim-3 overexpression enhances tumor cell growth, whereas Tim-3 inhibition on malignant hepatocytes by anti-Tim-3 antibodies or RNAi suppresses tumor growth both in vitro and in Tim-3 knockout mice. Mechanistically, the hepatocyte-Tim-3 receptor activates NF-κB phosphorylation, which in turn stimulates IL-6 secretion and STAT3 phosphorylation. Our results identify tumor cell-intrinsic functions of Tim-3 in tumorigenesis and suggest that blocking Tim-3 in tumor cells might contribute to the clinical efficacy of anti-Tim-3 antibody treatment in the future tumor therapy.