Crespo Eugenia, Loureiro Liliana R, Stammberger Antonia, Hoffmann Lydia, Berndt Nicole, Hoffmann Anja, Dagostino Claudia, Soto Karla E G, Rupp Luise, Arndt Claudia, Schneider Martin, Ball Claudia R, Bachmann Michael, Schmitz Marc, Feldmann Anja
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany.
NPJ Precis Oncol. 2025 Feb 9;9(1):42. doi: 10.1038/s41698-025-00828-6.
Applying CAR T-cell therapy to treat solid tumors is especially challenging due to the immunosuppressive tumor microenvironment (TME). While our modular RevCAR system enhances the safety and controllability of CAR T-cell therapy, effectively targeting solid tumors remains difficult. Since PD-L1 is an immune checkpoint frequently upregulated by cancer cells and their microenvironment, it is a relevant target for solid tumors. Here, we introduce a novel PD-L1 RevTM capable of redirecting RevCAR T-cells to specifically target and kill PD-L1-expressing tumor cells, becoming activated and secreting pro-inflammatory cytokines. This is shown in vitro with monolayer and 3D models, including patient-derived cultures, and in vivo. Furthermore, we demonstrate in vitro and in vivo an AND-gated targeting of cells simultaneously expressing PD-L1 and another tumor-associated antigen by the Dual RevCAR system. Our findings suggest that RevCAR-mediated targeting of PD-L1 could be a promising therapeutic approach for modulating the TME and improving solid tumor treatment.
由于免疫抑制性肿瘤微环境(TME),应用嵌合抗原受体(CAR)T细胞疗法治疗实体瘤尤其具有挑战性。虽然我们的模块化RevCAR系统提高了CAR T细胞疗法的安全性和可控性,但有效靶向实体瘤仍然困难。由于程序性死亡配体1(PD-L1)是一种经常被癌细胞及其微环境上调的免疫检查点,它是实体瘤的一个相关靶点。在此,我们引入了一种新型的PD-L1 RevTM,它能够重定向RevCAR T细胞,以特异性靶向并杀死表达PD-L1的肿瘤细胞,使其激活并分泌促炎细胞因子。这在体外的单层和三维模型(包括患者来源的培养物)以及体内得到了证实。此外,我们在体外和体内证明了双RevCAR系统对同时表达PD-L1和另一种肿瘤相关抗原的细胞的与门控靶向。我们的研究结果表明,RevCAR介导的对PD-L1的靶向可能是一种有前途的治疗方法,用于调节肿瘤微环境和改善实体瘤治疗。
NPJ Precis Oncol. 2025-2-9
Front Immunol. 2023
Cancer Gene Ther. 2024-9
Phenomics. 2023-10-4
Front Immunol. 2023
Nat Rev Clin Oncol. 2023-6
JACC CardioOncol. 2022-12-20