Combining Vγ9Vδ2 T Cells with a Lipophilic Bisphosphonate Efficiently Kills Activated Hepatic Stellate Cells.
Combining Vγ9Vδ2 T Cells with a Lipophilic Bisphosphonate Efficiently Kills Activated Hepatic Stellate Cells.
复制标题
将 Vγ9Vγ2 T 细胞与亲脂性双磷酸盐结合可有效杀死活化的肝星状细胞
DOI：
10.3389/fimmu.2017.01381
复制
发表时间：
2017
影响因子：
7.3
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Zhou X;Gu Y;Xiao H;Kang N;Xie Y;Zhang G;Shi Y;Hu X;Oldfield E;Zhang X;Zhang Y
活化的肝星状细胞(AHSCs)现在被证实是人类肝损伤中纤维化的中心驱动因素。在慢性或反复损伤的情况下，可能会发生纤维化、肝硬变和肝细胞癌(HCC)，因此有兴趣下调AHSCs的活性以治疗这些疾病。在此，我们报道了肝硬变患者V-γ-9V-δ-2T细胞的减少，这促使我们研究V-γ-9V-δ-2T细胞与AHSC之间可能的相互作用。我们发现Vγ9Vδ2T细胞对AHSCs有杀伤作用，当BPH1236(骨吸收药物唑来膦酸盐的亲脂类似物)处理AHSCs时，杀伤作用增强。Transwell实验和原子力显微镜显示，细胞毒性是通过细胞与细胞之间的直接接触而介导的，BPH1236增加了AHSC与Vγ9Vδ2T细胞之间的黏附。机制上，BPH1236通过抑制法尼基二磷酸合成酶，导致磷酸抗原异戊烯基二磷酸积聚，并被Vγ9Vδ2T细胞识别。细胞溶解过程在很大程度上依赖于穿孔素/颗粒酶B途径。在RAG2−/−γc−/−免疫缺陷小鼠模型中，我们发现Vγ9Vδ2T细胞定位于肝脏，当与BPH-1236联合使用时，不仅可以杀死原位AHSC，还可以杀死原位肝癌肿瘤。总而言之，我们的结果首次验证了一种新的免疫治疗策略的概念，该策略使用过继转移的Vγ9Vδ2T细胞，结合亲脂性双膦酸盐治疗纤维化-肝硬化-肝癌疾病。
Activated hepatic stellate cells (aHSCs) are now established as a central driver of fibrosis in human liver injury. In the presence of chronic or repeated injury, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) can occur, so there is interest in down-regulating aHSCs activity in order to treat these diseases. Here, we report that Vγ9Vδ2 T cells are reduced in patients with liver cirrhosis, stimulating us to investigate possible interactions between Vγ9Vδ2 T cells and aHSCs. We find that Vγ9Vδ2 T cells kill aHSCs and killing is enhanced when aHSCs are pretreated with BPH-1236, a lipophilic analog of the bone resorption drug zoledronate. Cytotoxicity is mediated by direct cell-to-cell contact as shown by Transwell experiments and atomic force microscopy, with BPH-1236 increasing the adhesion between aHSCs and Vγ9Vδ2 T cells. Mechanistically, BPH-1236 functions by inhibiting farnesyl diphosphate synthase, leading to accumulation of the phosphoantigen isopentenyl diphosphate and recognition by Vγ9Vδ2 T cells. The cytolytic process is largely dependent on the perforin/granzyme B pathway. In a Rag2−/−γc−/− immune-deficient mouse model, we find that Vγ9Vδ2 T cells home-in to the liver, and when accompanied by BPH-1236, kill not only orthotopic aHSCs but also orthotopic HCC tumors. Collectively, our results provide the first proof-of-concept of a novel immunotherapeutic strategy for the treatment of fibrosis–cirrhosis–HCC diseases using adoptively transferred Vγ9Vδ2 T cells, combined with a lipophilic bisphosphonate.