通过增强CCL2介导的CAR-T细胞迁移来靶向非小细胞肺癌的脑转移灶
Targeting brain lesions of non-small cell lung cancer by enhancing CCL2-mediated CAR-T cell migration.
作者信息
Li Hongxia, Harrison Emily B, Li Huizhong, Hirabayashi Koichi, Chen Jing, Li Qi-Xiang, Gunn Jared, Weiss Jared, Savoldo Barbara, Parker Joel S, Pecot Chad V, Dotti Gianpietro, Du Hongwei
机构信息
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
出版信息
Nat Commun. 2022 Apr 20;13(1):2154. doi: 10.1038/s41467-022-29647-0.
Metastatic non-small cell lung cancer (NSCLC) remains largely incurable and the prognosis is extremely poor once it spreads to the brain. In particular, in patients with brain metastases, the blood brain barrier (BBB) remains a significant obstacle for the biodistribution of antitumor drugs and immune cells. Here we report that chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR) exhibit antitumor activity in vitro against tumor cell lines and lung cancer organoids, and in vivo in xenotransplant models of orthotopic and metastatic NSCLC. The co-expression of the CCL2 receptor CCR2b in B7-H3.CAR-T cells, significantly improves their capability of passing the BBB, providing enhanced antitumor activity against brain tumor lesions. These findings indicate that leveraging T-cell chemotaxis through CCR2b co-expression represents a strategy to improve the efficacy of adoptive T-cell therapies in patients with solid tumors presenting with brain metastases.
转移性非小细胞肺癌（NSCLC）基本上仍无法治愈，一旦扩散到脑部，预后极差。特别是，在脑转移患者中，血脑屏障（BBB）仍然是抗肿瘤药物和免疫细胞生物分布的重大障碍。在此我们报告，靶向B7-H3的嵌合抗原受体（CAR）T细胞（B7-H3.CAR）在体外对肿瘤细胞系和肺癌类器官具有抗肿瘤活性，在原位和转移性NSCLC异种移植模型中体内也具有抗肿瘤活性。B7-H3.CAR-T细胞中CCL2受体CCR2b的共表达显著提高了它们穿过血脑屏障的能力，增强了对脑肿瘤病变的抗肿瘤活性。这些发现表明，通过CCR2b共表达利用T细胞趋化作用是一种提高过继性T细胞疗法对伴有脑转移实体瘤患者疗效的策略。
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