Department of Head & Neck Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
State Key Laboratory of Biotherapy/Collaborative Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Gene Ther. 2023 May;30(5):411-420. doi: 10.1038/s41434-021-00257-7. Epub 2021 May 6.
Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacies in treating hematopoietic malignancies, but not in the solid tumors. Incorporating costimulatory signaling domains, such as ICOS or 4-1BB, can positively influence CAR-T cell functions and then the immune responses. These CAR-engineered T cells have showed their enhanced persistence and effector functions with improved antitumor activities, and provided a new approach for the treatment of solid tumors. Here, we designed novel 2nd generation CARs with a costimulatory signaling molecule, dectin-1. The impacts of dectin-1 signaling domain on CAR-T cells were evaluated in vitro and in vivo. Our data show that in vitro cytokine secretions by HER2 or CD19 specific CAR-T cells increase significantly via incorporating this dectin-1 signaling domain. Additional properties of these novel CAR-T cells are affected by this costimulatory domain. Compared with a popular reference (i.e., anti-HER2 CAR-T cells with 4-1BB), in vitro T cell functions and in vivo antitumor activity of the dectin-1 engineered CAR-T cells are similar to the 4-1BB based, and both are discrete to the mock T cells. Furthermore, we found that the CAR-T cells with dectin-1 show distinct phenotype and exhaustion marker expression. These collective results suggest that the incorporation of this new signaling domain, dectin-1, into the CARs may provide the clinical potential of the CAR-T cells through this signaling domain in treating solid tumors.
嵌合抗原受体 T (CAR-T) 细胞疗法在治疗血液恶性肿瘤方面已显示出显著疗效，但在实体肿瘤方面效果不佳。共表达共刺激信号结构域，如 ICOSL 或 4-1BB，可正向影响 CAR-T 细胞功能和免疫反应。这些经过基因工程改造的 CAR-T 细胞表现出增强的持久性和效应功能，具有更好的抗肿瘤活性，为治疗实体肿瘤提供了新的方法。在这里，我们设计了具有共刺激信号分子 dectin-1 的新型第二代 CAR。在体外和体内评估了 dectin-1 信号结构域对 CAR-T 细胞的影响。我们的数据表明，通过共表达该 dectin-1 信号结构域，HER2 或 CD19 特异性 CAR-T 细胞体外细胞因子的分泌显著增加。这些新型 CAR-T 细胞的其他特性受该共刺激结构域的影响。与一种流行的对照（即，具有 4-1BB 的抗 HER2 CAR-T 细胞）相比，dectin-1 工程化 CAR-T 细胞的体外 T 细胞功能和体内抗肿瘤活性与基于 4-1BB 的相似，并且都与模拟 T 细胞不同。此外，我们发现带有 dectin-1 的 CAR-T 细胞表现出独特的表型和耗竭标志物表达。这些综合结果表明，在 CAR 中加入这种新的信号结构域 dectin-1，可能通过该信号结构域为 CAR-T 细胞治疗实体肿瘤提供临床潜力。
