PDF(Pubmed)
Abstract：
In recent years, in the development of emerging immunotherapy, B7-H3 is also termed as CD276 and has become a novel chimeric antigen receptor (CAR)-T target against glioma and other tumours, and aroused extensive attention. However, B7-H3 has three isoforms (2, 3 and 4Ig) with the controversial expression and elusive function in tumour especially glioma. The current study mainly focuses on the regulatory factors and related mechanisms of generation of different B7-H3 isoforms. First, we have determined that 2Ig is dominant in glioma with high malignancy, and 4Ig is widely expressed, whereas 3Ig shows negative expression in all glioma. Next, we have further found that RNA binding protein annexin A2 (ANXA2) is essential for B7-H3 isoform maintenance, but fail to determine the choice of 4Ig or 2Ig. RNA methyltransferase NOP2/Sun RNA methyltransferase 2 (NSUN2) and 5-methylcytosine reader Y-box binding protein 1 (YBX1) facilitate the production of 2Ig. Our findings have uncovered a series of factors (ANXA2/NSUN2/YBX1) that can determine the alternative generation of different isoforms of B7-H3 in glioma. Our result aims to help peers gain a clearer understanding of the expression and regulatory mechanisms of B7H3 in tumour patients, and to provide better strategies for designing B7H3 as a target in immunotherapy.
摘要：
近年来,在新兴免疫疗法的发展中，B7-H3也被称为CD276，并已成为针对神经胶质瘤和其他肿瘤的新型嵌合抗原受体（CAR）-T靶标。引起了广泛的关注。然而,B7-H3具有三种亚型（2、3和4Ig），在肿瘤尤其是神经胶质瘤中具有争议的表达和难以捉摸的功能。目前的研究主要集中在不同B7-H3亚型产生的调控因子和相关机制。首先,我们已经确定2Ig在恶性程度较高的神经胶质瘤中占主导地位，4Ig广泛表达，而3Ig在所有胶质瘤中均显示阴性表达。接下来,我们进一步发现RNA结合蛋白膜联蛋白A2（ANXA2）是B7-H3亚型维持所必需的，但未能确定选择4Ig或2Ig。RNA甲基转移酶NOP2/SunRNA甲基转移酶2（NSUN2）和5-甲基胞嘧啶读取器Y-box结合蛋白1（YBX1）促进2Ig的产生。我们的发现揭示了一系列因素（ANXA2/NSUN2/YBX1），可以确定神经胶质瘤中B7-H3不同亚型的替代产生。我们的结果旨在帮助同行更清楚地了解肿瘤患者中B7H3的表达和调节机制。并为B7H3作为免疫治疗靶点的设计提供更好的策略。
