CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
CD4⁺ T 细胞中 BCL6 过表达诱导 Tfh 样转分化并增强 CAR-T 疗法在胰腺癌中的抗肿瘤效能
英文原题：BCL6 overexpression in CD4(+) T cells induces Tfh-like transdifferentiation and enhances antitumor efficiency of CAR-T therapy in pancreatic cancer.
查看英文原题
BCL6 overexpression in CD4(+) T cells induces Tfh-like transdifferentiation and enhances antitumor efficiency of CAR-T therapy in pancreatic cancer.
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中文摘要
胰腺导管腺癌是典型“冷肿瘤”，免疫细胞浸润少且微环境抑制性强。研究者此前发现少量滤泡辅助T细胞可通过招募其他免疫细胞增强胰腺癌抗肿瘤反应。本研究在CD4阳性T细胞中异位表达BCL6，体外诱导其转化为滤泡辅助样T细胞（iTfh）。所得细胞可像内源性Tfh一样招募CD8阳性T细胞。研究进一步以靶向间皮素或EPHA2的CAR修饰iTfh，显著提高共培养CD8细胞浸润和抗肿瘤杀伤。异种移植模型中，CAR-iTfh与CAR-CD8联合较常规CAR-CD4与CAR-CD8组合更有效抑制肿瘤并改善生存。研究揭示辅助T细胞分化可塑性，拓展了细胞疗法中Tfh样细胞来源，并提出更有效的CAR-T 细胞组成方案。
展开英文摘要原文
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 T helper 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.
论文信息
- 作者
- Lin X、Dai Z、Tasiheng Y、Zhang R、Wang R、Dong J、Chen Y、Ma M
- 第一作者单位
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.China
- 通讯作者单位
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. Electronic address: liuchen@fudanpci.org.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Biochimica et biophysica acta. Molecular basis of disease2024 Oct
- 原文标识
- PubMed 38986820 · DOI 10.1016/j.bbadis.2024.167346