PDF(Pubmed)
Abstract：
PDL1 blockade therapy holds great promise in cancer immunotherapy. Ultrasound imaging of PDL1 expression in the tumor is of great importance in predicting the therapeutic efficacy. As a proof-of-concept study, a novel ultrasound contrast agent has been innovated here to image and block PDL1 in the tumor tissue. Briefly, extracellular vesicles (EVs) are engineered to display truncated PD1 (tPD1) on the surface to bind PDL1 with high affinity by fusion to EV-abundant transmembrane protein PTGFRN. The engineered EVs are then encapsulated with Ca(HCO3)2 via electroporation and designated as Gp-EVtPD1, which would recognize PDL1 highly expressed cells and produce gas in the endosomes and lysosomes. On the one hand, the echogenic signal intensity correlates well with the PDL1 expression and immune response inhibition in the tumor. On the other hand, during the trajectory of Gp-EVtPD1 in the recipient cells, tPD1 on the EV binds PDL1 and triggers the PDL1 endocytosis and degradation in endosomes/lysosomes in a sequential manner, and thus boosts the anti-tumor immunity of cytotoxic T cells. In summary, Gp-EVtPD1 serves as a novel ultrasound contrast agent and blocker of PDL1, which might be of great advantage in imaging PDL1 expression and conquering immune checkpoint blocker resistance.
摘要：
PDL1阻断疗法在癌症免疫疗法中具有巨大的前景。肿瘤中PDL1表达的超声成像对预测治疗效果具有重要意义。作为一项概念验证研究，一种新的超声造影剂已经在这里被创新成像和阻断肿瘤组织中的PDL1。简而言之，细胞外囊泡（EV）被设计为在表面上显示截短的PD1（tPD1），以通过与EV丰富的跨膜蛋白PTGFRN融合而以高亲和力结合PDL1。然后通过电穿孔用Ca（HCO3）2封装工程EV，并命名为Gp-EVtPD1，它将识别PDL1高表达的细胞并在内体和溶酶体中产生气体。一方面,回声信号强度与肿瘤中PDL1的表达和免疫反应抑制密切相关。另一方面,在Gp-EVtPD1在受体细胞中的轨迹过程中，EV上的tPD1结合PDL1，并以顺序方式触发内体/溶酶体中的PDL1内吞和降解，从而增强细胞毒性T细胞的抗肿瘤免疫力。总之,Gp-EVtPD1作为一种新型的超声造影剂和PDL1阻断剂，在成像PDL1表达和克服免疫检查点阻断剂抵抗方面可能具有很大的优势。
