有“癌癥之王”之稱的肝癌復發(fā)率高,，其主要原因就是人體內的正常細胞斗不過癌細胞,。為何斗不過？一直是個謎,。近日,，華中科技大學同濟醫(yī)學院附屬協和醫(yī)院院長王國斌教授研究組與美國密歇根大學教授鄒偉平歷經3年研究，在全球率先發(fā)現其中機理,，成果文章已發(fā)表在國際著名學術期刊《肝臟病學》（Hepatology ）上,。
據了解，在人體正常免疫狀態(tài)下,，肝臟組織中一種吞噬細菌的細胞——枯否細胞，可不斷激活一種免疫細胞——T細胞,，來殺死肝癌細胞,。通俗來講,，就好比一把手槍(枯否細胞)射出子彈(T細胞)，擊中目標(肝癌細胞),。然而,，肝癌患者體內這把“手槍”的扳機失靈了。研究發(fā)現,，有乙肝病史的肝癌患者體內,，“枯否細胞”表達Galectin-9陽性信息，“Th1細胞”(T細胞的一種)表現Tim-3陽性信息,，這兩種信息的結合,，阻止了Th1細胞的增殖，導致了T細胞喪失了“攻擊”肝癌細胞的功能,。
“如果阻止這兩種信息結合，T細胞就有活力殺死肝癌細胞,。”王國斌介紹說,，目前已找到阻止上述信息結合的方法，尚在初步試驗階段,。如果成功,，人類將有望根治肝癌。（生物谷Bioon.com）
doi:10.1002/hep.25777
PMC:
PMID:
Tim‐3/galectin‐9 signaling pathway mediates T cell dysfunction and predicts poor prognosis in patients with HBV‐associated hepatocellular carcinoma
Li, Hang; Wu, Ke; Tao, Kaixiong; Chen, Libo; Zheng, Qichang; Lu, Xiaoming; Liu, Jun; Shi, Liang; Liu, Chuanqiao; Wang, Guobin; Zou, Weiping
The interaction between T cell immunoglobulin- and mucin-domain-containing molecule (Tim-3) expressed on Th1 cells, and its ligand, galectin-9, negatively regulates Th1-mediated immune responses. However, it is poorly understood if and how 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 Tim-3/galectin-9 pathway in patients with hepatitis B virus (HBV)-associated HCC. We have 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 co-localization of Tim-3+ T cells and galectin-9+ KCs in HCC. Functional studies demonstrated that blockade of 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 showed that the numbers of Tim-3+ tumor infiltrating cells were negatively associated with patient survival. Our work demonstrates that Tim-3/galectin-9 signaling pathway mediates T cell senescence in HBV-associated HCC. The data suggests that this pathway could be an immunotherapeutic target in patients with HBV-associated HCC.
