CXCL10/CXCR3 signaling mobilized-regulatory T cells promote liver tumor recurrence after transplantation

作者：Chang Xian Li, Chang Chun Ling, Yan Shao, Aimin Xu, Xiang Cheng Li, TP Ng, Xiao Bing Liu, Yuen Yuen, Qi Xiang, Hui Liu, Jiang Liu, Oscar W.H. Yeung, Xin Xiang Yang, Qing Sheng Liu, Yin Fan Lam, Yuan Zhai, Chung Mau Lo, Kwan Man · 发表于：Journal of Hepatology · 年份：2016 · DOI：10.1016/j.jhep.2016.05.032 · 被引用次数：175 · 研究领域：Chemokine receptors and signaling、Cancer Immunotherapy and Biomarkers、Hepatocellular Carcinoma Treatment and Prognosis

Background & Aims Liver graft injury and tumor recurrence are the major challenges of liver transplantation for the patients with hepatocellular carcinoma (HCC). Here, we aimed to explore the role and mechanism of liver graft injury mobilizing regulatory T cells (Tregs), which lead to late phase tumor recurrence after liver transplantation. Methods The correlation among tumor recurrence, liver graft injury and Tregs mobilization were studied in 257 liver transplant recipients with HCC and orthotopic rat liver transplantation models. The direct roles of CXCL10/CXCR3 signaling on Tregs mobilization and tumor recurrence were investigated in CXCL10 −/− and CXCR3 −/− mice models with hepatic IR injury. Results Clinically, patients received the graft with graft weight ratio (GWR) <60% had higher HCC recurrence after liver transplantation than the recipients with GWR ⩾60% graft. More circulating Tregs and higher intragraft TLR4/CXCL10/CXCR3 levels were detected in recipients with GWR <60% graft. These results were further validated in rat transplantation model. Foxp3 + cells and expressions of TLR4, CXCL10, TGFβ, CTLA-4 and CD274 were increased in rat liver tumor tissues from small-for-size graft group. In mouse model, the mobilization and recruitment of Tregs were decreased in TLR4 −/− , CXCL10 −/− and CXCR3 −/− mice compared to wild-type mice. Moreover, less CXCR3 + Tregs were recruited into liver in CXCL10 −/− mice after hepatic IR injury. The knockout of CXCL10 and depletion of ...