有“癌癥之王”之稱的肝癌復(fù)發(fā)率高，其主要原因就是人體內(nèi)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(xué)同濟醫(yī)學(xué)院附屬協(xié)和醫(yī)院院長王國斌教授研究組與美國密歇根大學(xué)教授鄒偉平歷經(jīng)3年研究,，在全球率先發(fā)現(xiàn)其中機理，成果文章已發(fā)表在國際著名學(xué)術(shù)期刊《肝臟病學(xué)》（Hepatology ）上,。
據(jù)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(biāo)(肝癌細胞)。然而,，肝癌患者體內(nèi)這把“手槍”的扳機失靈了,。研究發(fā)現(xiàn)，有乙肝病史的肝癌患者體內(nèi),，“枯否細胞”表達Galectin-9陽性信息,，“Th1細胞”(T細胞的一種)表現(xiàn)Tim-3陽性信息，這兩種信息的結(jié)合,，阻止了Th1細胞的增殖,，導(dǎo)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(jié)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(jié)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.
