瞬时 CAR T 细胞对实体瘤中的癌胚糖胺聚糖具有特异性。
Transient CAR T cells with specificity to oncofetal glycosaminoglycans in solid tumors.
发表日期：2024 Oct 15
作者：
Nastaran Khazamipour, Htoo Zarni Oo, Nader Al-Nakouzi, Mona Marzban, Nasrin Khazamipour, Morgan E Roberts, Negin Farivar, Igor Moskalev, Joey Lo, Fariba Ghaidi, Irina Nelepcu, Alireza Moeen, Sarah Truong, Robert Dagil, Swati Choudhary, Tobias Gustavsson, Beibei Zhai, Sabine Heitzender, Ali Salanti, Poul H Sorensen, Mads Daugaard
来源：
EMBO Molecular Medicine
摘要：
由于糖表位的复杂性和获得特定亚型结合的选择有限，糖胺聚糖通常不被优先考虑作为合成免疫疗法的靶标。实体瘤表达经癌胎儿硫酸软骨素（CS）修饰的蛋白聚糖，这种修饰通常仅限于胎盘。在这里，我们报告了对癌胎儿 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”，以靶向表达癌胎儿 CS 的肿瘤细胞。虽然未武装的 CAR T 细胞在靶细胞存在的情况下仍保持不活跃状态，但携带 VAR2 的 CAR T 细胞表现出强大的激活能力以及在体外消除多种肿瘤细胞类型的能力。 CAR T 细胞的细胞毒性与 CAR 可用的 rVAR2 浓度成正比，为微调 CAR T 细胞活性提供了潜在的分子控制。在体内，武装的 CAR T 细胞快速靶向膀胱肿瘤并提高荷瘤小鼠的存活率。因此，我们的工作表明癌症限制性糖胺聚糖可以作为 CAR T 细胞疗法的潜在靶标。© 2024。作者。
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.© 2024. The Author(s).