文章:

CAR工程化淋巴细胞的持久性受FAS配体-FAS自身调节回路调控

CAR-engineered lymphocyte persistence is governed by a FAS ligand–FAS autoregulatory circuit

原文发布日期：2025-07-22

英文摘要：

 Chimeric antigen receptor (CAR)-engineered lymphocytes treat B cell malignancies; however, limited persistence can restrain the full therapeutic potential of this approach. FAS ligand (FAS-L)/FAS interactions govern lymphocyte homeostasis. Knowledge of which cells express FAS-L in patients with cancer and whether these sources compromise CAR persistence remains incomplete. Here, we constructed a single-cell atlas of diverse cancers to identify cellular subsets expressing FASLG, the gene encoding FAS-L. We discovered that FASLG expression is limited primarily to endogenous T cells, natural killer (NK) cells and CAR-T cells, while tumor and stromal cell expression is minimal. To establish whether CAR-T and CAR-NK cell survival is FAS-L regulated, we performed competitive fitness assays using FAS-dominant negative receptor (ΔFAS)-modified lymphocytes. Following transfer, ΔFAS-expressing CAR-T/CAR-NK cells became enriched, a phenomenon that mechanistically was reverted through FASLG knockout. By contrast, FASLG was dispensable for CAR-mediated tumor killing. In multiple models in female mice, ΔFAS coexpression enhanced antitumor efficacy. Together, these findings reveal that CAR-engineered lymphocyte persistence is governed by a FAS-L/FAS autoregulatory circuit.

摘要翻译：

嵌合抗原受体（CAR）修饰的淋巴细胞已应用于B细胞恶性肿瘤的治疗，但细胞持久性不足限制了该疗法的全部潜力。FAS配体（FAS-L）与FAS的相互作用调控淋巴细胞稳态。目前关于癌症患者中哪些细胞表达FAS-L、以及这些细胞来源是否会损害CAR细胞持久性，仍缺乏系统认知。本研究通过构建多癌种单细胞图谱，首次系统鉴定了表达FASLG基因（编码FAS-L）的细胞亚群。研究发现FASLG表达主要局限于内源性T细胞、自然杀伤（NK）细胞及CAR-T细胞，而肿瘤细胞与基质细胞几乎不表达。为验证CAR-T和CAR-NK细胞存活是否受FAS-L调控，我们采用表达FAS显性阴性受体（ΔFAS）的淋巴细胞进行竞争性适应度实验。过继转移后，表达ΔFAS的CAR-T/CAR-NK细胞呈现选择性富集，该现象可通过FASLG基因敲除实现机制性逆转。值得注意的是，FASLG对CAR介导的肿瘤杀伤功能非必需。在雌性小鼠多模型中，ΔFAS共表达显著增强了抗肿瘤疗效。这些发现共同揭示：CAR修饰淋巴细胞的持久性受FAS-L/FAS自体调节回路调控。

原文链接：

 https://www.nature.com/articles/s43018-025-01009-x