Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma

Authors

  • Hang Li,

    1. Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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    • *These authors contributed equally to this work.

  • Ke Wu,

    1. Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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    • *These authors contributed equally to this work.

  • Kaixiong Tao,

    1. Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Libo Chen,

    1. Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Qichang Zheng,

    1. Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Xiaoming Lu,

    1. Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Jun Liu,

    1. Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Liang Shi,

    1. Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Chuanqiao Liu,

    1. Wuhan Blood Center, Wuhan, China
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  • Guobin Wang,

    Corresponding author
    1. Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    • Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China
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  • Weiping Zou

    Corresponding author
    1. Department of Surgery, Graduate Programs in Immunology and Tumor Biology, Comprehensive Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI
    • Department of Surgery, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109
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  • Potential conflict of interest: Nothing to report.

Abstract

The interaction between T cell immunoglobulin- and mucin-domain-containing molecule (Tim-3) expressed on T helper 1 (Th1) cells, and its ligand, galectin-9, negatively regulates Th1-mediated immune responses. However, it is poorly understood if and how the Tim-3/galectin-9 signaling pathway is involved in immune escape in patients with hepatocellular carcinoma (HCC). Here we studied the expression, function, and regulation of the Tim-3/galectin-9 pathway in patients with hepatitis B virus (HBV)-associated HCC. We detected different levels of galectin-9 expression on antigen-presenting cell (APC) subsets including Kupffer cells (KCs), myeloid dendritic cells (DCs), and plasmacytoid DCs in HCC. The highest galectin-9 expression was on KCs in HCC islets, not in the adjacent tissues. Furthermore, Tim-3 expression was increased on CD4+ and CD8+ T cells in HCC as compared to the adjacent tissues, and Tim-3+ T cells were replicative senescent and expressed surface and genetic markers for senescence. Interestingly, tumor-infiltrating T-cell-derived interferon (IFN)-γ stimulated the expression of galectin-9 on APCs in the HCC microenvironment. Immunofluorescence staining revealed a colocalization of Tim-3+ T cells and galectin-9+ KCs in HCC. Functional studies demonstrated that blockade of the Tim-3/galectin-9 signaling pathway importantly increased the functionality of tumor-infiltrating Tim-3+ T cells as shown by increased T-cell proliferation and effector cytokine production. Finally, we show that the numbers of Tim-3+ tumor-infiltrating cells were negatively associated with patient survival. Conclusion: Our work demonstrates that the Tim-3/galectin-9 signaling pathway mediates T-cell senescence in HBV-associated HCC. The data suggest that this pathway could be an immunotherapeutic target in patients with HBV-associated HCC. (HEPATOLOGY 2012)

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