肿瘤细胞治疗研究
英文原题：Depletion of an immature cord blood NK subset reverses trogocytosis-driven CAR NK dysfunction.
这些发现定义了供者亚群驱动的CAR NK功能障碍机制，并提供了一种提高抗肿瘤效力的生产策略。
异体CAR工程化NK细胞可实现可扩展的即用型治疗，但供者异质性仍是影响疗效一致性的主要障碍。基于我们在脐血来源CAR NK细胞方面的临床经验，我们发现一种未成熟的CD16-CD161-双阴性（DN）NK亚群与不良结局相关。经CAR工程化后，DN来源的NK细胞仍保持低功能状态，却表现出过度活跃的胞吐吞噬作用，积累高水平同源抗原，并在产品内形成胞吐吞噬抗原池（TAS），从而将CAR结合从肿瘤靶标转移，并促进产品内靶向非肿瘤的相互作用。因此，暴露于TAS的CD16+CD161+双阳性（DP）效应细胞发生持续活化、代谢应激、自相残杀、活力下降、程序性细胞死亡以及进行性耗竭，最终导致持久性和肿瘤控制受损。在制造前去除DN可消除TAS，并在血液肿瘤和实体瘤模型中恢复DP抗肿瘤活性。总之，这些发现定义了供者亚群驱动的CAR NK功能障碍机制，并提供了一种提高抗肿瘤效力的制造策略。
Allogeneic CAR-engineered NK cells enable scalable off-the-shelf therapy, yet donor heterogeneity remains a major barrier to consistent potency. Building on our clinical experience with cord blood-derived CAR NK cells, we identified an immature CD16 - CD161 - double-negative (DN) NK subset associated with poor outcomes. Following CAR engineering, DN-derived NK cells remained hypofunctional yet exhibited exaggerated trogocytosis, accumulating high levels of cognate antigen and forming an intra-product trogocytic-antigen sink (TAS) that diverted CAR engagement from tumor targets and promoted on-target off-tumor interactions within the product. Consequently, CD16 + CD161 + double-positive (DP) effectors exposed to the TAS underwent sustained activation, metabolic stress, fratricide, reduced viability, programmed cell death, and progressive exhaustion, culminating in impaired persistence and tumor control. Pre-manufacturing DN depletion eliminated the TAS and restored DP antitumor activity across hematologic and solid tumor models. Together, these findings define a donor subset-driven mechanism of CAR NK dysfunction and provide a manufacturing strategy to improve antitumor potency.
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