Celastrol increases osteosarcoma cell lysis by γδ T cells through up-regulation of death receptors.
Celastrol increases osteosarcoma cell lysis by γδ T cells through up-regulation of death receptors.
复制标题
雷公藤红素通过上调死亡受体来增加 γδ T 细胞对骨肉瘤细胞的溶解
DOI：
10.18632/oncotarget.12756
复制
发表时间：
2016-12-20
期刊：
影响因子：
--
通讯作者：
Wang R
中科院分区：
文献类型：
--
作者：
Li Z;Zhang J;Tang J;Wang R
γδ T细胞已被证明在广泛的肿瘤实体中表现出深刻的抗肿瘤作用，包括OS。然而，对γδ T细胞的耐药性是OS治疗中的一个严重问题。本研究探讨了雷公藤红素对OS细胞株（HOS、U2OS）死亡受体4/5 （DR4/5）表达及γδ T细胞裂解癌细胞的影响。结果表明，celastrol增加了DR4/5在HOS和U2OS中的转录，导致细胞表面增加，DR4/5蛋白总表达增加。在体外研究中，雷公藤红素可使OS细胞系或自体OS细胞对健康供体来源或OS患者来源的γδ T细胞毒性致敏。DR4/5分子的诱导增加了γδ T细胞对HOS和U2OS的裂解，而添加阻断性TRAIL抗体可以消除这种裂解。重要的是，小剂量的雷公藤红素没有改变γδ T细胞的细胞毒活性。综上所述，我们的数据表明，celastrol上调了OS细胞上的DR4/5，负责细胞间TRAIL/APO-2L交联，从而增加了γδ T细胞对癌细胞的裂解。这些结果提示celastrol在OS中的临床评价，特别是与采用过继性γδ T细胞转移的免疫治疗方法相结合。
γδ T cells has been shown to exhibit profound antitumor effects in a broad range of tumor entities, including OS. However, resistance to γδ T cells is a serious problem in the management of OS. This study investigates the impact of celastrol on the expression of death receptors 4/5 (DR4/5) on OS cell lines (HOS, U2OS) and cancer cell lysis by γδ T cells. The results showed that celastrol increased transcription of DR4/5 in HOS and U2OS, leading to increased cell surface, and total DR4/5 protein expression. Celastrol sensitizes OS cell lines or autologous OS cells to healthy donors-derived or OS patient-derived γδ T cell cytotoxicity in vitro. The induction of DR4/5 molecules increased lysis of HOS and U2OS by γδ T cells which was abolished by addition of a blocking TRAIL antibody. Importantly, the cytotoxic activity of γδ T cells was unaltered by small-dose celastrol. Taken together, our data show that celastrol up-regulated DR4/5 on OS cells to be responsible for intercellular TRAIL/APO-2L crosslink that confers increased cancer cell lysis by γδ T cells. These results suggest the clinical evaluation of celastrol in OS, especially in combination with immunotherapy approaches employing adoptive γδ T cell transfer.