有“癌症之王”之称的肝癌复发率高,其主要原因就是人体内的正常细胞斗不过癌细胞。为何斗不过?一直是个谜。近日,华中科技大学同济医学院附属协和医院院长王国斌教授研究组与美国密歇根大学教授邹伟平历经3年研究,在全球率先发现其中机理,成果文章已发表在国际著名学术期刊《肝脏病学》(Hepatology )上。
据了解,在人体正常免疫状态下,肝脏组织中一种吞噬细菌的细胞——枯否细胞,可不断激活一种免疫细胞——T细胞,来杀死肝癌细胞。通俗来讲,就好比一把手枪(枯否细胞)射出子弹(T细胞),击中目标(肝癌细胞)。然而,肝癌患者体内这把“手枪”的扳机失灵了。研究发现,有乙肝病史的肝癌患者体内,“枯否细胞”表达Galectin-9阳性信息,“Th1细胞”(T细胞的一种)表现Tim-3阳性信息,这两种信息的结合,阻止了Th1细胞的增殖,导致了T细胞丧失了“攻击”肝癌细胞的功能。
“如果阻止这两种信息结合,T细胞就有活力杀死肝癌细胞。”王国斌介绍说,目前已找到阻止上述信息结合的方法,尚在初步试验阶段。如果成功,人类将有望根治肝癌。(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.