尽管我们之前的数据表明，紧密蛋白 18 亚型 2 (CLDN18.2) 靶向嵌合抗原受体 (CAR) T 细胞在 CLDN18.2 阳性胃癌中显示出显着的临床疗效，但其在胰腺导管腺癌 (PDAC) 中的疗效有限。肿瘤微环境（TME）是CAR-T功效的主要障碍之一，重塑TME可能是克服这一障碍的可能方法。 PDAC的TME的特点是大量的癌症相关成纤维细胞（CAF），阻碍了CLDN18.2靶向的CAR-T细胞的浸润和功能。成纤维细胞活化蛋白α（FAP）的表达是活性CAF的重要特征，为消除CAF提供了潜在的靶点。在本研究中，我们生成了10个FAP/CLDN 18.2双靶向CAR-T细胞并评估了它们的抗肿瘤能力与传统的CAR-T细胞相比，一些双靶向CAR-T细胞在小鼠胰腺癌中表现出更好的治疗效果。此外，具有更好抗肿瘤效果的双靶点CAR-T细胞可以抑制骨髓源性抑制细胞（MDSC）的募集，从而改善免疫抑制性TME，从而有助于CD8 T细胞的存活。此外，双靶向CAR-T细胞通过转化TGF-β依赖的方式减少了T细胞的耗竭。双靶向CAR-T细胞获得了T效应功能的增强、T细胞耗竭的抑制以及肿瘤微环境的改善。我们的研究结果为 PDAC 中双靶向 FAP/CLDN 18.2 CAR-T 细胞治疗提供了理论依据。© 2024 英国药理学会。

Although our previous data indicated that claudin 18 isoform 2 (CLDN18.2)-targeted chimeric antigen receptor (CAR) T cells displayed remarkable clinical efficacy in CLDN18.2-positive gastric cancer, their efficacy is limited in pancreatic ductal adenocarcinoma (PDAC). The tumour microenvironment (TME) is one of the main obstacles to the efficacy of CAR-T and remodelling the TME may be a possible way to overcome this obstacle. The TME of PDAC is characterized by abundant cancer-related fibroblasts (CAFs), which hinder the infiltration and function of CLDN18.2-targeted CAR-T cells. The expression of fibroblast activation protein alpha (FAP) is an important feature of active CAFs, providing potential targets for eliminating CAFs.In this study, we generated 10 FAP/CLDN 18.2 dual-targeted CAR-T cells and evaluated their anti-tumour ability in vitro and in vivo.Compared with conventional CAR-T cells, some dual-targeted CAR-T cells showed improved therapeutic effects in mouse pancreatic cancers. Further, dual-targeted CAR-T cells with better anti-tumour effect could suppress the recruitment of myeloid-derived suppressor cells (MDSCs) to improve the immunosuppressive TME, which contributes to the survival of CD8+ T cells. Moreover, dual-targeted CAR-T cells reduced the exhaustion of T cells in transforming TGF-β dependent manner.The dual-targeted CAR-T cells obtained enhancement of T effector function, inhibition of T cell exhaustion, and improvement of tumour microenvironment. Our findings provide a theoretical rationale for dual-targeted FAP/CLDN 18.2 CAR-T cells therapy in PDAC.© 2024 British Pharmacological Society.