Rossig Claudia, Kailayangiri Sareetha, Jamitzky Silke, Altvater Bianca
Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany.
Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Muenster, Muenster, Germany.
Front Oncol. 2018 Nov 12;8:513. doi: 10.3389/fonc.2018.00513. eCollection 2018.
Application of the CAR targeting strategy in solid tumors is challenged by the need for adequate target antigens. As a consequence of their tissue origin, embryonal cancers can aberrantly express membrane-anchored gangliosides. These are carbohydrate molecules consisting of a glycosphingolipid linked to sialic acids residues. The best-known example is the abundant expression of ganglioside G on the cell surface of neuroblastomas which derive from G-positive neuroectoderm. Gangliosides are involved in various cellular functions, including signal transduction, cell proliferation, differentiation, adhesion and cell death. In addition, transformation of human cells to cancer cells can be associated with distinct glycosylation profiles which provide advantages for tumor growth and dissemination and can serve as immune targets. Both gangliosides and aberrant glycosylation of proteins escape the direct molecular and proteomic screening strategies currently applied to identify further immune targets in cancers. Due to their highly restricted expression and their functional roles in the malignant behavior, they are attractive targets for immune engineering strategies. G-redirected CAR T cells have shown activity in clinical phase I/II trials in neuroblastoma and next-generation studies are ongoing. Further carbohydrate targets for CAR T cells in preclinical development are O-acetyl-G, NeuGc-GM3 (N-glycolyl GM3), G, SSEA-4, and oncofetal glycosylation variants. This review summarizes knowledge on the role and function of some membrane-expressed non-protein antigens, including gangliosides and abnormal protein glycosylation patterns, and discusses their potential to serve as a CAR targets in pediatric solid cancers.
嵌合抗原受体（CAR）靶向策略在实体瘤中的应用受到对充足靶抗原需求的挑战。由于其组织起源，胚胎癌可异常表达膜锚定神经节苷脂。这些是由与唾液酸残基相连的糖鞘脂组成的碳水化合物分子。最著名的例子是源自G阳性神经外胚层的神经母细胞瘤细胞表面大量表达神经节苷脂G。神经节苷脂参与多种细胞功能，包括信号转导、细胞增殖、分化、黏附和细胞死亡。此外，人类细胞向癌细胞的转化可能与独特的糖基化谱相关，这为肿瘤生长和扩散提供了优势，并可作为免疫靶点。神经节苷脂和蛋白质的异常糖基化都逃避了目前用于识别癌症中更多免疫靶点的直接分子和蛋白质组学筛选策略。由于它们的高度限制性表达及其在恶性行为中的功能作用，它们是免疫工程策略的有吸引力的靶点。重定向至G的CAR T细胞在神经母细胞瘤的临床I/II期试验中已显示出活性，下一代研究正在进行中。临床前开发中CAR T细胞的其他碳水化合物靶点包括O-乙酰-G、NeuGc-GM3（N-羟乙酰神经节苷脂GM3）、G、阶段特异性胚胎抗原-4（SSEA-4）和癌胚糖基化变体。本综述总结了一些膜表达非蛋白质抗原的作用和功能的知识，包括神经节苷脂和异常蛋白质糖基化模式，并讨论了它们作为儿科实体癌中CAR靶点的潜力。
