肿瘤细胞治疗研究
英文原题：Overcoming extracellular vesicle-mediated fratricide improves CAR T cell treatment against solid tumors.
我们的研究揭示了一种限制 CAR-T 细胞功能的机制，并提出了一种改进的肿瘤治疗策略。
嵌合抗原受体（CAR）T细胞对实体瘤的疗效有限。CAR-T耐药的分子机制尚待阐明，需开发新策略改善治疗结局。本研究发现，实体瘤可通过上调携带肿瘤抗原的小细胞外囊泡分泌作出应答；这些囊泡可水平转移至CAR-T细胞，引发抗原识别并导致CAR-T细胞自相残杀。以主要颗粒酶B抑制剂Serpin B9对CAR-T细胞进行装甲化改造，可减少细胞间自相残杀，并提高雌性小鼠中的细胞活力、肿瘤浸润和抗肿瘤活性。此外，联合抗程序性死亡蛋白1（PD-1）抗体治疗实体瘤时，Serpin B9装甲化CAR-T细胞的疗效优于亲本CAR-T细胞。本研究揭示了一种限制CAR-T细胞功能的机制，并提出改善肿瘤治疗的策略。
The efficacy of chimeric antigen receptor (CAR) T cells against solid tumors is limited. The molecular mechanisms underlying CAR T cell resistance are yet to be elucidated and new strategies need to be developed to improve treatment outcomes. Here we report that solid tumors respond to CAR T cells by upregulating the secretion of small extracellular vesicles carrying tumor antigens, which are horizontally transferred to CAR T cells, leading to antigen recognition and CAR T cell fratricide. Engineered CAR T cells armored with Serpin B9, a major granzyme B inhibitor, show decreased fratricide and increased vitality, tumor infiltration, and antitumor activity in female mice. Moreover, Serpin B9-armored CAR T cells show higher efficacy than parental CAR T cells in treating solid tumors when combined with the anti-programmed death 1 antibody. Our study demonstrates a mechanism that limits CAR T cell function and suggests an improved strategy in tumor treatment.
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