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

Oncogenevolume 37pages24562468 (2018) | Download Citation

Abstract

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.

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Acknowledgements

This work was supported by grants from the National Key Research and Development Program (No. 2016YFE0127000), the National Natural Science Fund for Outstanding Youth Fund (81425012), the National Science Foundation of China (No. 81672425, 81425012, 81372211, 91529305), Key Research & Development Plan of Shandong Province (2016ZDJS07A17, 2017GSF18185).

Author contributions

C.M.A., X.L., and L.G. designed and supervised the study and experiments, analyzed the data, and co-wrote the manuscript. H.Z., Y.S., H.Y., and Z.L. developed the methodologies, performed the experiments, analyzed the data. All authors read and approved the final manuscript.

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Author notes

  1. These authors contributed equally: Hualin Zhang, Yang Song.

Affiliations

  1. Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory for Infection and Immunity of Shandong Province and Department of Immunology School of Basic Medicine, Shandong University, Jinan, Shandong, 250012, China

    • Hualin Zhang
    • , Yang Song
    • , Lifen Gao
    • , Xiaohong Liang
    •  & Chunhong Ma
  2. Department of Nephrology, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China

    • Huimin Yang
  3. Department of Pathology and Pathophysiology, Shandong University, Jinan, Shandong, 250012, China

    • Zhiyan Liu
  4. State Key Laboratory of Microbial Technology, Shandong University, Shandong, China

    • Chunhong Ma

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Xiaohong Liang or Chunhong Ma.

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https://doi.org/10.1038/s41388-018-0140-4

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