title: Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Li
authors.forename: Ke
authors.initials: K
authors.lastname: Wu
authors.forename: Kaixiong
authors.initials: K
authors.lastname: Tao
authors.forename: Libo
authors.initials: L
authors.lastname: Chen
authors.forename: Qichang
authors.initials: Q
authors.lastname: Zheng
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Lu
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Liang
authors.initials: L
authors.lastname: Shi
authors.forename: Chuanqiao
authors.initials: C
authors.lastname: Liu
authors.forename: Guobin
authors.initials: G
authors.lastname: Wang
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000401:mortality / Q000473:pathology / Q000821:virology*; D002478:Cells, Cultured; D005260:Female; D037161:Galectins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D000072597:Hepatitis A Virus Cellular Receptor 2; D006509:Hepatitis B / Q000276:immunology* / Q000503:physiopathology; D006515:Hepatitis B virus / Q000502:physiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism; D008113:Liver Neoplasms / Q000401:mortality / Q000473:pathology / Q000821:virology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D012494:Sampling Studies; D015398:Signal Transduction / Q000235:genetics; D018709:Statistics, Nonparametric; D016019:Survival Analysis
chemical_list: D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105032:LGALS9 protein, human; D008565:Membrane Proteins