Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xinsi Road No. 569th, Xi'an, 710038, P. R. China.
Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Shaanxi, 710032, P. R. China.
Adv Sci (Weinh). 2024 Mar;11(12):e2305891. doi: 10.1002/advs.202305891. Epub 2024 Jan 23.
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(HCO) via electroporation and designated as Gp-EV, 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-EV 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-EV 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.
PDL1 阻断疗法在癌症免疫疗法中具有巨大的潜力。超声成像技术可用于检测肿瘤中 PDL1 的表达,这对于预测治疗效果非常重要。作为概念验证研究,我们创新性地开发了一种新型超声对比剂,用于对肿瘤组织中的 PDL1 进行成像和阻断。简而言之,我们通过融合到富含 EV 的跨膜蛋白 PTGFRN 上,将细胞外囊泡 (EVs) 工程化为在表面展示截断的 PD1(tPD1),从而以高亲和力结合 PDL1。然后,通过电穿孔将工程化的 EV 包裹在 Ca(HCO)中,并将其命名为 Gp-EV,它可以识别高表达 PDL1 的细胞,并在内体和溶酶体中产生气体。一方面,声反射信号强度与肿瘤中 PDL1 的表达和免疫反应抑制密切相关。另一方面,在 Gp-EV 进入受体细胞的过程中,EV 上的 tPD1 与 PDL1 结合,并依次触发 PDL1 内吞和降解,从而增强了细胞毒性 T 细胞的抗肿瘤免疫。总之,Gp-EV 既可用作新型超声对比剂,也可用作 PDL1 阻断剂,在成像 PDL1 表达和克服免疫检查点抑制剂耐药性方面具有很大的优势。
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