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Abstract：
Anti-cluster of differentiation (CD) 3 × α programmed death-ligand 1 (PD-L1) bispecific T-cell engager (BsTE)-bound T-cells (BsTE:T) are a promising new cancer treatment agent. However, the mechanisms of action of bispecific antibody-armed activated T-cells are poorly understood. Therefore, this study aimed to investigate the anti-tumor mechanism and efficacy of BsTE:T. The BsTE:T migration was assessed in vivo and in vitro using syngeneic and xenogeneic tumor models, flow cytometry, immunofluorescence staining, transwell migration assays, microfluidic chips, Exo View R100, western blotting, and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 technology. In murine B16 melanoma, MC38 colon cancer, and human multiple myeloma cells, BsTE:T exhibited superior tumor elimination relative to that of T-cells or BsTE alone. Moreover, BsTE:T migration into tumors was significantly enhanced owing to the presence of PD-L1 in tumor cells and secretion of PD-L1-containing exosomes. Furthermore, increased infiltration of CD44highCD62Llow effector memory CD8+ T-cells into tumors was closely associated with the anti-tumor effect of BsTE:T. Therefore, BsTE:T is an innovative potential anti-tumor therapy, and exosomal PD-L1 plays a crucial role both in vitro and in vivo in the anti-tumor activity of BsTE:T.
摘要：
抗分化簇（CD）3×α程序性死亡配体1（PD-L1）双特异性T细胞衔接剂（BsTE）结合的T细胞（BsTE：T）是一种有前途的新型癌症治疗剂。然而,双特异性抗体武装的活化T细胞的作用机制知之甚少.因此,本研究旨在探讨BsTE的抗肿瘤机制和疗效。使用同基因和异种肿瘤模型在体内和体外评估BsTE：T迁移，流式细胞术,免疫荧光染色，transwell迁移测定，微流控芯片，ExoViewR100，西方印迹，和成簇的规则间隔短回文重复序列（CRISPR）/CRISPR相关蛋白9技术。在鼠B16黑色素瘤中，MC38结肠癌，和人类多发性骨髓瘤细胞，BsTE:T相对于T细胞或单独的BsTE表现出优异的肿瘤消除。此外，BsTE:由于肿瘤细胞中PD-L1的存在和含有PD-L1的外泌体的分泌,T迁移到肿瘤中显著增强。此外，CD44highCD62L低效应记忆CD8+T细胞在肿瘤中的浸润增加与BsTE的抗肿瘤作用密切相关：因此,BsTE：T是一种创新的潜在抗肿瘤疗法，外泌体PD-L1在体外和体内BsTE：T的抗肿瘤活性中起着至关重要的作用。
