PDAC是一种典型的“冷肿瘤”，其特点是免疫细胞浸润低、免疫微环境抑制。我们之前观察到存在一组罕见的滤泡辅助 T 细胞 (Tfh)，它们可以通过在 PDAC 中招募其他免疫细胞来增强抗肿瘤免疫反应。在本研究中，我们在CD4 T细胞中异位表达BCL6，并在体外成功诱导Tfh样转分化。这种策略提供了丰富的 Tfh 样细胞 (iTfhs)，可以像内源性 Tfhs 一样招募 CD8 T 细胞。随后，针对MSL（间皮素）和EPHA2（肝配蛋白受体A2）的嵌合抗原受体（CAR）被用于修饰iTfh细胞，并且CAR-iTfh细胞显着改善了共培养的CD8 T细胞的浸润和抗肿瘤细胞毒性。之后，CAR-iTfh的联合给药

PDAC is a typical "cold tumor" characterized by low immune cell infiltration and a suppressive immune microenvironment. We previously observed the existence of a rare group of follicular helper T cells (Tfh) that could enhance antitumor immune responses by recruiting other immune cells in PDAC. In this study, we ectopically expressed BCL6 in CD4+ T cells, and successfully induced Tfh-like transdifferentiation in vitro. This strategy provided abundant Tfh-like cells (iTfhs) that can recruit CD8+ T cells like endogenous Tfhs. Subsequently, Chimeric Antigen Receptors (CARs) against both MSL (Mesothelin) and EPHA2 (Ephrin receptor A2) were used to modify iTfh cells, and the CAR-iTfh cells significantly improved infiltration and antitumor cytotoxicity of co-cultured CD8+ T cells. After that, combinatory administration of CAR-iTfh & CAR-CD8 T cell therapy displayed a better effect in repressing the PDAC tumors in xenograft mouse models, compared to conventional CAR-CD4 & CAR-CD8 combinations, and the models received the CAR-iTfh & CAR-CD8 T cells displayed a significantly improved survival rate. Our study revealed the plasticity of Thelper differentiation, expanded the source of Tfh-like cells for cell therapy, and demonstrated a novel and potentially more efficient cellular composition for CAR-T therapy.Copyright © 2024. Published by Elsevier B.V.