T lymphocytes expressing the switchable chimeric Fc receptor CD64 exhibit augmented persistence and antitumor activity
T lymphocytes expressing the switchable chimeric Fc receptor CD64 exhibit augmented persistence and antitumor activity
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DOI：
10.1016/j.celrep.2023.112797
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发表时间：
2023-07-11
期刊：
影响因子：
8.8
通讯作者：
Li，Peng
中科院分区：
文献类型：
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作者：
Cui，Yuanbin;Yuan，Tingjie;Li，Peng
嵌合抗原受体 (CAR) T 细胞疗法在治疗实体瘤方面缺乏持久疗效，且存在“靶向、肿瘤外”毒性。因此，设计了一种抗体引导的可切换CAR载体，即由CD64胞外结构域组成的嵌合Fc受体CD64（CFR64）。与具有高亲和力 CD16 变体 (CD16v) 或 CD32A 作为胞外结构域的 CFR T 细胞相比，表达 CFR64 的 T 细胞对癌细胞具有更强的细胞毒性。与传统 CAR T 细胞相比，CFR64 T 细胞还表现出更好的长期细胞毒性和对 T 细胞耗竭的抵抗力。与抗 HER2 CAR T 细胞相比，曲妥珠单抗由 CFR64 建立的免疫突触 (IS) 更稳定，下游信号传导强度更低。此外，CFR64 T 细胞在刺激反应中表现出融合线粒体，而 CARH2 T 细胞主要含有点状线粒体。这些结果表明，CFR64 T 细胞可以作为一种可控的工程化 T 细胞疗法，具有持久的持久性和长期的抗肿瘤活性。
Chimeric antigen receptor (CAR) T cell therapy lacks persistent efficacy with "on-target, off-tumor" toxicities for treating solid tumors. Thus, an antibody-guided switchable CAR vector, the chimeric Fc receptor CD64 (CFR64), composed of a CD64 extracellular domain, is designed. T cells expressing CFR64 exert more robust cytotoxicity against cancer cells than CFR T cells with high-affinity CD16 variant (CD16v) or CD32A as their extracellular domains. CFR64 T cells also exhibit better long-term cytotoxicity and resistance to T cell exhaustion compared with conventional CAR T cells. With trastuzumab, the immunological synapse (IS) established by CFR64 is more stable with lower intensity induction of downstream signaling than anti-HER2 CAR T cells. Moreover, CFR64 T cells exhibit fused mitochondria in response to stimulation, while CARH2 T cells contain predominantly punctate mitochondria. These results show that CFR64 T cells may serve as a controllable engineered T cell therapy with prolonged persistence and long-term antitumor activity.