Zhong Wenqun, Qin Zhiyuan, Yu Ziyan, Yang Jingbo, Yan Dongdong, Engel Nils W, Sheppard Neil C, Fan Yi, Radhakrishnan Ravi, Xu Xiaowei, Ma Leyuan, Fuchs Serge Y, June Carl H, Guo Wei
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nat Cancer. 2025 Apr 15. doi: 10.1038/s43018-025-00949-8.
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.
嵌合抗原受体（CAR）T细胞对实体瘤的疗效有限。CAR T细胞耐药的分子机制尚待阐明，需要开发新策略来改善治疗效果。在此我们报告，实体瘤通过上调携带肿瘤抗原的小细胞外囊泡的分泌来响应CAR T细胞，这些小细胞外囊泡会水平转移至CAR T细胞，导致抗原识别及CAR T细胞自相残杀。用主要的颗粒酶B抑制剂丝氨酸蛋白酶抑制剂B9（Serpin B9）武装的工程化CAR T细胞在雌性小鼠中表现出自相残杀减少、活力增强、肿瘤浸润增加及抗肿瘤活性增强。此外，当与抗程序性死亡1抗体联合使用时，Serpin B9武装的CAR T细胞在治疗实体瘤方面比亲本CAR T细胞具有更高的疗效。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。
