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.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
PD1-TLR10 融合蛋白增强 CAR-T 细胞在结肠癌中的抗肿瘤疗效
英文原题：PD1-TLR10 fusion protein enhances the antitumor efficacy of CAR-T cells in colon cancer.
查看英文原题
PD1-TLR10 fusion protein enhances the antitumor efficacy of CAR-T cells in colon cancer.
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研究概要
我们的研究表明，装载合理设计的 PD1-TLR10 融合蛋白的 CEA CAR-T 在结肠癌中疗效更优。
中文摘要
背景
免疫抑制性微环境会降低CAR-T 细胞治疗实体瘤的疗效。将抑制性检查点蛋白胞外结构域与刺激分子胞质结构域融合形成的融合蛋白，可能通过逆转抑制信号提高CAR-T 细胞疗效。
方法
为构建优化的PD1-TLR10融合蛋白，研究者分别使用PD1、CD28或TLR10来源的跨膜结构域，将PD1胞外结构域与TLR10胞内结构域连接。融合蛋白与第二代抗CEA CAR共表达于同一逆转录病毒载体中。研究者在体外和体内评估融合蛋白增强型CAR-T 细胞的效应功能和疗效。
结果
PD1-TLR10增强型CEA CAR-T 细胞对CEA阳性肿瘤细胞表现出更强细胞毒性和细胞因子释放。具体而言，含有TLR10跨膜结构域的融合蛋白CAR-T 细胞在异种移植小鼠模型中显示更佳抗肿瘤活性。
结论
本研究表明，采用合理设计的PD1-TLR10融合蛋白增强CEA CAR-T 可改善其结肠癌治疗效果。
展开英文摘要原文
BACKGROUND
The immunosuppressive microenvironment negatively affects the efficacy of chimeric antigen receptor T (CAR-T) cells in solid tumors. Fusion protein that combining extracellular domain of inhibitory checkpoint protein and the cytoplasmic domain of stimulatory molecule may improve the efficacy of CAR-T cells by reversing the suppressive signals.
METHODS
To generate optimal PD1-TLR10 fusion proteins, PD1 extracellular domain and TLR10 intracellular domain were connected by transmembrane domain from PD1, CD28, or TLR10, respectively. The fusion protein was co-expressed with second generation anti-CEA CAR in the same retroviral vector. The effector function and the efficacy of fusion protein armored CAR-T cells was evaluated in vitro and in vivo.
RESULTS
PD1-TLR10 armored CEA CAR-T cells showed stronger cytotoxicity and cytokine release against CEA-positive tumor cells. Specifically, CAR-T cells with fusion protein containing TLR10 transmembrane domain demonstrated better anti-tumor activity in xenograft mouse model.
CONCLUSION
Our study demonstrated that CEA CAR-T armored with rational designed PD1-TLR10 fusion protein had improved efficacy in colon cancer.
论文信息
- 作者
- Peng Y、Huang Z、Wu Y、Wu T、Lu J、Zhang J、Liu X
- 第一作者单位
- Department of Bioengineering, School of Life Sciences, Fudan University, Songhu Road 2005, 200438 Shanghai, China; TriArm Therapeutics, Niudun Road 200, 201203 Shanghai, China.China
- 通讯作者单位
- TriArm Therapeutics, Niudun Road 200, 201203 Shanghai, China. Electronic address: xiang.liu@triarmbio.com.China
- 期刊
- International immunopharmacology2025 Feb 20
- 原文标识
- PubMed 39818091 · DOI 10.1016/j.intimp.2025.114083