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Tim‐3/galectin‐9 signaling pathway mediates T‐cell dysfunction and predicts poor prognosis in patients with hepatitis B virus‐associated hepatocellular carcinoma
dc.contributor.authorLi, Hangen_US
dc.contributor.authorWu, Keen_US
dc.contributor.authorTao, Kaixiongen_US
dc.contributor.authorChen, Liboen_US
dc.contributor.authorZheng, Qichangen_US
dc.contributor.authorLu, Xiaomingen_US
dc.contributor.authorLiu, Junen_US
dc.contributor.authorShi, Liangen_US
dc.contributor.authorLiu, Chuanqiaoen_US
dc.contributor.authorWang, Guobinen_US
dc.contributor.authorZou, Weipingen_US
dc.date.accessioned2012-11-07T17:04:38Z
dc.date.available2013-11-15T16:44:23Zen_US
dc.date.issued2012-10en_US
dc.identifier.citationLi, Hang; Wu, Ke; Tao, Kaixiong; Chen, Libo; Zheng, Qichang; Lu, Xiaoming; Liu, Jun; Shi, Liang; Liu, Chuanqiao; Wang, Guobin; Zou, Weiping (2012). "Tim‐3/galectin‐9 signaling pathway mediates T‐cell dysfunction and predicts poor prognosis in patients with hepatitis B virus‐associated hepatocellular carcinoma ." Hepatology 56(4): 1342-1351. <http://hdl.handle.net/2027.42/94269>en_US
dc.identifier.issn0270-9139en_US
dc.identifier.issn1527-3350en_US
dc.identifier.urihttps://hdl.handle.net/2027.42/94269
dc.description.abstractThe 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. (H EPATOLOGY 2012)en_US
dc.publisherWiley Subscription Services, Inc., A Wiley Companyen_US
dc.titleTim‐3/galectin‐9 signaling pathway mediates T‐cell dysfunction and predicts poor prognosis in patients with hepatitis B virus‐associated hepatocellular carcinomaen_US
dc.typeArticleen_US
dc.rights.robotsIndexNoFollowen_US
dc.subject.hlbsecondlevelInternal Medicine and Specialtiesen_US
dc.subject.hlbtoplevelHealth Sciencesen_US
dc.description.peerreviewedPeer Revieweden_US
dc.contributor.affiliationumDepartment of Surgery, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109en_US
dc.contributor.affiliationumDepartment of Surgery, Graduate Programs in Immunology and Tumor Biology, Comprehensive Cancer Center, University of Michigan School of Medicine, Ann Arbor, MIen_US
dc.contributor.affiliationotherWuhan Blood Center, Wuhan, Chinaen_US
dc.contributor.affiliationotherDepartment of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Chinaen_US
dc.contributor.affiliationotherDepartment of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Chinaen_US
dc.contributor.affiliationotherDepartment of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Chinaen_US
dc.identifier.pmid22505239en_US
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/94269/1/25777_ftp.pdf
dc.identifier.doi10.1002/hep.25777en_US
dc.identifier.sourceHepatologyen_US
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dc.owningcollnameInterdisciplinary and Peer-Reviewed


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