Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
Vancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.
EMBO Mol Med. 2024 Nov;16(11):2775-2794. doi: 10.1038/s44321-024-00153-8. Epub 2024 Oct 15.
Glycosaminoglycans are often deprioritized as targets for synthetic immunotherapy due to the complexity of glyco-epitopes and limited options for obtaining specific subtype binding. Solid tumors express proteoglycans that are modified with oncofetal chondroitin sulfate (CS), a modification normally restricted to the placenta. Here, we report the design and functionality of transient chimeric antigen receptor (CAR) T cells with selectivity to oncofetal CS. Following expression in T cells, the CAR could be "armed" with recombinant VAR2CSA lectins (rVAR2) to target tumor cells expressing oncofetal CS. While unarmed CAR T cells remained inactive in the presence of target cells, VAR2-armed CAR T cells displayed robust activation and the ability to eliminate diverse tumor cell types in vitro. Cytotoxicity of the CAR T cells was proportional to the concentration of rVAR2 available to the CAR, offering a potential molecular handle to finetune CAR T cell activity. In vivo, armed CAR T cells rapidly targeted bladder tumors and increased the survival of tumor-bearing mice. Thus, our work indicates that cancer-restricted glycosaminoglycans may be exploited as potential targets for CAR T cell therapy.
糖胺聚糖通常因其糖基表位的复杂性和获得特定亚型结合的有限选择而被优先考虑用于合成免疫疗法。实体瘤表达经过修饰的蛋白聚糖，这些蛋白聚糖带有癌胎性软骨素硫酸盐（CS），这种修饰通常仅限于胎盘。在这里，我们报告了对癌胎性 CS 具有选择性的瞬时嵌合抗原受体（CAR）T 细胞的设计和功能。在 T 细胞中表达后，CAR 可以用重组 VAR2CSA 凝集素（rVAR2）“武装”，以靶向表达癌胎性 CS 的肿瘤细胞。在存在靶细胞的情况下，未武装的 CAR T 细胞仍然不活跃，而 VAR2 武装的 CAR T 细胞则表现出强大的激活能力，并能够在体外消除多种肿瘤细胞类型。CAR T 细胞的细胞毒性与 CAR 可用的 rVAR2 的浓度成正比，这为微调 CAR T 细胞活性提供了潜在的分子控制手段。在体内，武装的 CAR T 细胞迅速靶向膀胱肿瘤，并提高了荷瘤小鼠的存活率。因此，我们的工作表明，癌症特异性糖胺聚糖可能被用作 CAR T 细胞治疗的潜在靶点。
