肿瘤细胞治疗研究
英文原题：OX40-heparan sulfate binding facilitates CAR T cell penetration into solid tumors in mice.
尽管嵌合抗原受体（CAR）修饰的T细胞在治疗B细胞恶性肿瘤方面取得了巨大成功，但它们在对抗实体瘤方面仅显示出有限的疗效。
尽管嵌合抗原受体（CAR）修饰的T细胞在治疗B细胞恶性肿瘤方面取得了巨大成功，但其对实体瘤的疗效有限。在此，我们通过整合一个不依赖抗原的OX40设计了一种CAR，该CAR对多种实体瘤表现出优越的抗肿瘤疗效。我们通过基于CRISPR-Cas9的全基因组筛选意外发现，硫酸乙酰肝素是OX40的配体。我们发现硫酸乙酰肝素在生化和细胞水平上可直接结合OX40，并且硫酸乙酰肝素与OX40的相互作用激活了AKT、MAPK和NF-κB信号通路。在功能上，硫酸乙酰肝素-OX40相互作用增强了细胞黏附以及CAR T细胞与肿瘤细胞的功能性结合亲和力。在体内，表达OX40的CAR T细胞表现出增强的实体瘤浸润和持久性，且依赖于OX40-硫酸乙酰肝素相互作用。我们的发现揭示了一种能够调节T细胞免疫并具有应用于CAR T细胞优化潜力的聚糖共刺激相互作用。
Although chimeric antigen receptor (CAR)-modified T cells have shown great success in treating B cell malignancies, they have demonstrated only limited efficacy against solid tumors. Here, we designed a CAR by integrating an antigen-independent OX40 that showed superior antitumor efficacy against multiple solid tumors. We unexpectedly found, through a CRISPR-Cas9-based whole-genome screen, that heparan sulfate is a ligand for OX40. We found that heparan sulfate can directly bind OX40 at the biochemical and cellular levels and that the interaction of heparan sulfate and OX40 activated the AKT, MAPK, and NF- B signaling pathways. Functionally, the heparan sulfate-OX40 interaction enhanced cell adhesion and CAR T cell functional binding avidity to tumor cells. In vivo, OX40-expressing CAR T cells exhibited increased solid tumor infiltration and persistence dependent on the OX40-heparan sulfate interaction. Our findings provide insights into a glycan-costimulation interaction that is capable of regulating T cell immunity and has potential application in CAR T cell optimization.
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