双靶向DLL3/CD56的CAR-T细胞中平行4-1BB信号触发适应性增殖与功能持久性以根除小细胞肺癌
Parallel 4-1BB Signaling in Dual DLL3/CD56-Targeting CAR-T Cells Triggers Adaptive Proliferation and Functional Persistence to Eradicate Small Cell Lung Cancer.
作者
作者单位
- West China Hospital of Sichuan University chengdu China.
- West China Hospital of Sichuan University Chengdu China.
- West China Hospital of Sichuan University chengdu, sichuan China.
- West China Hospital of Sichuan University Chengdu, Sichuan Province China.
- Army Medical University Chongqing China.
摘要
中文
肿瘤内有限的持久性和不足的增殖能力严重限制了嵌合抗原受体（CAR）-T细胞疗法在实体瘤中的疗效。本研究证明，共表达CD56嵌合转换受体（CSR）并整合平行4-1BB共刺激信号的DLL3靶向CAR-T细胞（DBBζ.CBB）可有效克服这些局限。在临床前小细胞肺癌（SCLC）模型中，DBBζ.CBB表现出持续的肿瘤浸润、延长的持久性以及优越的抗肿瘤活性。机制上，平行4-1BB信号通过促进早期扩增和记忆维持、在中间阶段驱动高度增殖的效应状态，并在后期延缓终末耗竭，从而动态调控CAR-T细胞命运，进而维持体内持久性并实现持久的抗肿瘤反应。在DBBζ.CBB所建立的肿瘤内T细胞库基础上，后续给予DLL3三特异性T细胞 engager（TriTCE）可进一步增强CD8+ T细胞浸润和整体活化，同时减轻耗竭和终末分化，从而协同增强肿瘤根除效果。综上，这些发现建立了一种具有临床转化潜力的联合策略框架，以增强CAR-T疗法在实体瘤中的疗效和持久性。
English
Limited intratumoral persistence and insufficient proliferative capacity severely restrict the efficacy of chimeric antigen receptor (CAR)-T cell therapies in solid tumors. Here, we demonstrated that DLL3-targeting CAR-T cells co-expressing a CD56 chimeric switch receptor (CSR) and incorporating parallel 4-1BB costimulatory signaling (DBBζ.CBB) effectively address these limitations. In preclinical small cell lung cancer (SCLC) models, DBBζ.CBB exhibited sustained tumor infiltration, prolonged persistence, and superior antitumor activity. Mechanistically, parallel 4-1BB signaling dynamically programed CAR-T cell fate by promoting early expansion and memory maintenance, driving a highly proliferative effector state at the intermediate stage, and delaying terminal exhaustion at the later stage, thereby sustaining in vivo persistence and enabling durable antitumor responses. Building upon the intratumoral T-cell pool established by DBBζ.CBB, subsequent DLL3 trispecific T-cell engager (TriTCE) administration synergistically enhanced tumor eradication by further boosting CD8+ T cell infiltration and overall activation while mitigating exhaustion and terminal differentiation. Collectively, these findings establish a clinically translatable combinatorial framework to enhance the efficacy and durability of CAR-T therapy in solid tumors.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 22.6
- 新锐分区
- 1区