瘤微环境的酶重塑增强了抗CEACAM5 CAR T细胞对结肠直肠癌的有效性
Debasis Banik1, Christopher J Ward2, Soura Chakraborty2
1Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
|January 22, 2026
概括
针对CEACAM5的CAR T细胞疗法在结直肠癌中是无效的,因为瘤是瘤.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 细胞生物学 细胞生物学
背景情况:
- 化学抗原受体 (CAR) T细胞疗法在血液癌症中表现有前途,但与固体瘤作斗争.
- 癌胚抗原相关细胞粘附分子5 (CEACAM5) 是一些固体瘤的向抗原,包括结直肠癌 (CRC).
- 现有的抗CEACAM5 CAR T细胞已经证明对CRC无效.
研究的目的:
- 研究CEACAM5向CAR T细胞和结直肠癌细胞之间的相互作用.
- 阐明抗CEACAM5CAR T细胞疗法在CRC治疗效率有限的原因.
- 确定增强CAR T细胞对CRC的有效性的策略.
主要方法:
- 使用光显微镜研究CAR T细胞和CRC细胞相互作用.
- 通过测量流量来评估CAR T细胞激活.
- 进行了细胞毒性测试,以评估抗瘤活性.
- 使用酶治疗 (素,氨酸酶) 来修改CRC细胞表面和葡萄糖.
- 在CRC细胞和患者组织上评估了CEACAM5的可访问性.
主要成果:
- 结肠直肠癌细胞具有比CAR T细胞更厚的葡萄糖,导致T细胞激活延迟.
- 卡尔T细胞激活是暂时的,由振荡的流体表明,随着细胞播种时间的延长而恶化.
- 细胞毒性随着CRC细胞播种时间的增加而显著降低,与可访问CEACAM5.5的减少相关.
- 用素或氨酸酶进行的蛋白质溶解治疗增加了CEACAM5的可用性,减少了葡萄糖的厚度,并恢复了持续的T细胞激活和细胞毒性.
- 酶治疗增强了CAR T细胞介导的细胞毒性和增加了TNF-α分泌.
结论:
- 厚厚的葡萄糖和CEACAM5在CRC细胞细胞间结处的封存阻碍了CAR T细胞的功能.
- 对CRC细胞表面的酶干扰增强了CAR T细胞的参与,激活和抗瘤功效.
- 用CAR T细胞向CEACAM5,可以通过解决瘤微环境和抗原可访问性来改善CRC治疗.
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