肿瘤细胞治疗研究
英文原题：CD2 costimulation bridges potent CAR-induced cytolysis and durable persistence.
CD2 costimulation bridges potent CAR-induced cytolysis and durable persistence.
CD2 胞质尾部与 CD3z 联合可提供平衡的共刺激，将快速的肿瘤减灭与 T 细胞持久性相偶联。
背景：目前第二代嵌合抗原受体（CAR）T细胞产品主要依赖CD28或4-1BB共刺激结构域，分别倾向于促进快速细胞毒作用或长期持久性，但鲜少能兼顾两者。临床前模型和回顾性分析显示，CD2-CD58结合与较好的临床前及临床应答相关，但CD2胞内信号的直接贡献尚未明确。 方法：我们将抗间皮素（SS1）和抗TnMUC1（5E5）CAR的共刺激结构域替换为人CD2胞质尾（CD2z），并与28z和BBz形式进行基准比较。采用瞬时mRNA表达，在无病毒基础性信号影响的条件下分析近端Ca²⁺通量和脱颗粒；采用慢病毒CAR开展持久功能实验。在体外和NSG异种移植模型中评估细胞因子释放、全基因组转录程序和抗肿瘤活性。 结果：CD2z CAR-T细胞的脱颗粒效率与其他含ζ结构域的CAR相当，Ca²⁺通量信号则介于28z和BBz CAR之间。慢病毒转导的CD2z CAR可释放偏Th1型的细胞因子谱，细胞毒性与28z相当，尽管急性细胞因子释放较低。转录组分析显示，CD2z细胞处于早期效应记忆状态：糖酵解、mTORC1和TNFα-NF-κB特征上调，而与28z相比，耗竭相关上调特征选择性减少。体内实验中，单次CD2z输注在60天观察期内使皮下间皮素阳性间皮瘤和原位TnMUC1阳性胰腺肿瘤显著、持久消退。其肿瘤控制与28z相当，早期清除肿瘤的速度快于BBz，同时支持与BBz类似的外周T细胞持久性。 结论：CD2胞质尾与CD3ζ组合可提供均衡的共刺激，将快速肿瘤减负与T细胞持久性结合起来。因此，CD2z可能成为新一代CAR-T治疗中替代经典CD28和4-1BB模块的一种简单、灵活方案。
BACKGROUND: Current second-generation CAR T cell products rely on CD28 or 4-1BB costimulatory domains, additions that respectively favor rapid cytolysis or long-term persistence, but rarely both. Preclinical modeling and retrospective analysis have linked CD2-CD58 engagement to superior preclinical and clinical responses, yet the direct contribution of CD2 intracellular signaling remains undefined. METHODS: We replaced the costimulatory domain of anti-mesothelin (SS1) and anti-TnMUC1 (5E5) CARs with the human CD2 cytoplasmic tail (CD2z) and benchmarked them against 28z and BBz formats. Transient mRNA expression was used to profile proximal Ca 2+ flux and degranulation free of tonic viral signals; durable functional assays employed lentiviral CARs. Cytokine release, genome-wide transcriptional programs, and anti-tumor activity were assessed in vitro and in NSG xenograft models. RESULTS: CD2z CAR T cells degranulated as efficiently as other z-containing CARs and generated a Ca 2+ flux signal intermediate to 28z and BBz CARs. Lentiviral CD2z CARs released a Th1-skewed cytokine panel and matched 28z cytolysis despite a lower acute cytokine release. Transcriptomic analysis characterized CD2z cells in an early effector-memory state: glycolytic, mTORC1, and TNFa-NF- B hallmarks were upregulated, whereas exhaustion-up signatures were selectively depleted vs 28z. In vivo, a single CD2z infusion induced deep and durable tumor regressions over the 60-day observation period in subcutaneous mesothelin-positive mesothelioma and orthotopic TnMUC1-positive pancreatic tumor models, achieving tumor control comparable to 28z and more rapid early tumor clearance than BBz, while supporting peripheral T cell persistence similar to BBz. CONCLUSIONS: The CD2 cytoplasmic tail, in combination with CD3z, delivers balanced costimulation that couples brisk tumor debulking to T cell persistence. CD2z therefore may provide a simple, versatile alternative to canonical CD28 and 4-1BB modules for next-generation CAR T therapies.
MEMBER ACCOUNT
登录成功会直接打开下一页。
