NKT细胞及CD4+ T细胞上的CXCR6抑制肝细胞衰老以抑制肝癌
创作:aluba 审核:aluba 2019年07月03日
  • 野生型小鼠及CXCR6敲除小鼠诱导肝癌并活化NKT细胞,并收集肝硬化(n=43)患者、肝细胞癌(n=35)患者及健康人(n=25)的肝脏组织样本;
  • CXCR6敲除小鼠的肿瘤负荷显著高于野生型小鼠,肿瘤进展增加,肝内表达TNF-α及INF-γ的NKT细胞及CD4+ T细胞显著减少;
  • CXCR6敲除小鼠的衰老肝细胞显著增加,NKT细胞及CD4+ T细胞促进了衰老肝细胞的清除以抑制肝癌发生;
  • 肝细胞癌患者的癌旁组织中CXCR6相关淋巴细胞积累,少于肝硬化组织。
来自Gastroenterology上发表的一项最新研究,发现NKT细胞及CD4+ T细胞上的CXCR6促进了小鼠体内衰老肝细胞的清除,以抑制肝癌的发生。
Gastroenterology [IF:22.682]

CXCR6 Inhibits Hepatocarcinogenesis by Promoting Natural Killer T- and CD4 T-Cell-Dependent Control of Senescence

CXCR6通过促进NKT细胞及CD4+ T细胞依赖性的衰老调控抑制肝癌发生


2019-05-01, Article

Abstract & Authors:展开

BACKGROUND & AIMS: Inflammation in the liver provokes fibrosis, but inflammation is also important for tumor surveillance. Inhibitors of chemokine pathways, such as CXCL16 and CXCR6 regulation of lymphocyte trafficking, are being tested as antifibrotic agents, but their effects on the development of hepatocellular carcinoma (HCC) are unclear. We assessed the roles of CXCR6-dependent immune mechanisms in hepatocarcinogenesis.
METHODS: C57BL/6J wild-type (WT) mice and CXCR6-deficient mice (Cxcr6) were given injections of diethylnitrosamine (DEN) to induce liver cancer and α-galactosylceramide to activate natural killer T (NKT) cells. We also performed studies in mice with conditional, hepatocyte-specific deletion of NEMO, which develop inflammation-associated liver tumors (Nemo and NemoCxcr6 mice). We collected liver tissues from patients with cirrhosis (n = 43), HCC (n = 35), and neither of these diseases (control individuals, n = 25). Human and mouse liver tissues were analyzed by histology, immunohistochemistry, flow cytometry, RNA expression arrays (from sorted hepatic lymphocytes), and matrix-assisted laser desorption/ionization imaging. Bone marrow was transferred from Cxcr6 or WT mice to irradiated C57BL/6J mice, and spleen and liver cells were analyzed by flow cytometry. CD4 T cells or NKT cells were isolated from the spleen and liver of CD45.1 WT mice and transferred into CXCR6-deficient mice after DEN injection.
RESULTS: After DEN injection, CXCR6-deficient mice had a significantly higher tumor burden than WT mice and increased tumor progression, characterized by reduced intrahepatic numbers of invariant NKT and CD4 T cells that express tumor necrosis factor and interferon gamma. Livers of NemoCxcr6 mice had significantly more senescent hepatocytes than livers of Nemo mice. In studies of bone-marrow chimeras, adoptive cell transfer experiments, and analyses of Nemo mice, we found that NKT and CD4 T cells promote the removal of senescent hepatocytes to prevent hepatocarcinogenesis, and that this process required CXCR6. Injection of WT with α-galactosylceramide increased removal of senescent hepatocytes by NKT cells. We observed peritumoral accumulation of CXCR6-associated lymphocytes in human HCC, which appeared reduced compared with cirrhosis tissues.
CONCLUSIONS: In studies of mice with liver tumors, we found that CXCR6 mediated NKT-cell and CD4 T-cell removal of senescent hepatocytes. Antifibrotic strategies to reduce CXCR6 activity in liver, or to reduce inflammation or modulate the immune response, should be tested for their effects on hepatocarcinogenesis.

First Authors:
Jana C Mossanen

Correspondence Authors:
Frank Tacke

All Authors:
Jana C Mossanen,Marlene Kohlhepp,Alexander Wehr,Oliver Krenkel,Anke Liepelt,Anjali A Roeth,Diana Möckel,Felix Heymann,Twan Lammers,Nikolaus Gassler,Juliane Hermann,Joachim Jankowski,Ulf P Neumann,Tom Luedde,Christian Trautwein,Frank Tacke