Herpes Virus Entry Mediator Costimulation Signaling Enhances CAR T-cell Efficacy Against Solid Tumors Through Metabolic Reprogramming
Herpes Virus Entry Mediator Costimulation Signaling Enhances CAR T-cell Efficacy Against Solid Tumors Through Metabolic Reprogramming
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DOI：
10.1158/2326-6066.cir-22-0531
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发表时间：
2023-04-01
影响因子：
10.1
通讯作者：
Zhang，Qing
中科院分区：
文献类型：
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作者：
Sun，Shishuo;Huang，Chao;Zhang，Qing
4-1BB和CD 28的共刺激结构域（CSD）最广泛地用于嵌合抗原受体（CAR）工程化的T细胞中。这些CAR T细胞在血液恶性肿瘤的治疗中显示出令人鼓舞的疗效，但在实体瘤中的疗效有限。疱疹病毒进入介体（HVEM）是一种具有新型下游信号通路的共刺激分子。响应于靶细胞，具有HVEM CSD的CAR T细胞（HVEM-CAR T）在体外显示出比4-1BB-CAR T或CD 28-CAR T更稳健的细胞因子释放和细胞毒性。此外，HVEM-CAR T在几种小鼠肿瘤模型中显示出上级的治疗功效。从机制上讲，HVEM CSD赋予CAR T细胞与基于4- 1BB或基于CD 28的CAR T细胞相比减弱的耗竭，改善的功能和持久性，以及增强的肿瘤组织中的代谢活性。这些研究证实HVEM CSD具有改善CAR T细胞对实体瘤的治疗功效的潜力。
Costimulatory domains (CSD) of 4-1BB and CD28 are most widely used in chimeric antigen receptor (CAR)–engineered T cells. These CAR T cells have shown encouraging efficacy in the treatment of hematologic malignancies but have limited efficacy in solid tumors. The herpes virus entry mediator (HVEM) is a costimulatory molecule with a novel downstream signaling pathway. In response to target cells, CAR T cells with a HVEM CSD (HVEM-CAR T) displayed more robust cytokine release and cytotoxicity than 4-1BB-CAR T or CD28-CAR Tin vitro. Furthermore, HVEM-CAR T showed superior therapeutic efficacy in several mouse tumor models. Mechanistically, the HVEM CSD endowed CAR T cells with attenuated exhaustion, improved function and persistence, and enhanced metabolic activities in tumor tissue compared with 4-1BB–based or CD28-based CAR T cells. These studies establish that the HVEM CSD has the potential to improve the therapeutic efficacy of CAR T cells against solid tumors.