Zhang Na, Liu Xiaohong, Qin Juliang, Sun Yue, Xiong Hao, Lin Boxu, Liu Kexin, Tan Binghe, Zhang Chenglin, Huang Chenshen, Ren Shancheng, Liu Mingyao, Du Bing
Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China; BRL Medicine, Inc, Shanghai 201109, China.
Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Mol Ther. 2023 Sep 6;31(9):2575-2590. doi: 10.1016/j.ymthe.2023.06.015. Epub 2023 Jul 5.
Tertiary lymphoid structures (TLSs) in tumor tissues facilitate immune cell trafficking and cytotoxicity, which benefits survival and favorable responses in immune therapy. Here, we observed a high correlation of tumor necrosis factor superfamily member 14 (LIGHT) expression with TLS signature genes, which are all markers for immune cell accumulation and better prognosis, through retrieving RNA sequencing (RNA-seq) data from patients with cancer, suggesting the potential of LIGHT in reconstituting a high immune-infiltrated tumor microenvironment. Accordingly, LIGHT co-expressed chimeric antigen receptor T (LIGHT CAR-T) cells not only showed enhanced cytotoxicity and cytokine production but also improved CCL19 and CCL21 expression by surrounding cells. And the supernatant of LIGHT CAR-T cells promoted T cell migration in a paracrine manner. Furthermore, LIGHT CAR-T cells showed superior anti-tumor efficacy and improved infiltration in comparison with conventional CAR-T cells in immunodeficient NSG mice. Accordingly, murine LIGHT-OT-1 T cells normalized tumor blood vessels and enforced intratumoral lymphoid structures in C57BL/6 syngeneic tumor mouse models, implying the potential of LIGHT CAR-T in clinical application. Taken together, our data revealed a straightforward strategy to optimize trafficking and cytotoxicity of CAR-T cells by redirecting TLSs through LIGHT expression, which has great potential to expand and optimize the application of CAR-T therapy in solid tumors.
肿瘤组织中的三级淋巴结构（TLSs）促进免疫细胞运输和细胞毒性，这有利于免疫治疗中的生存和良好反应。在这里，我们通过检索癌症患者的RNA测序（RNA-seq）数据，观察到肿瘤坏死因子超家族成员14（LIGHT）表达与TLS特征基因高度相关，这些基因都是免疫细胞积累和更好预后的标志物，这表明LIGHT在重建高免疫浸润肿瘤微环境方面具有潜力。因此，共表达LIGHT的嵌合抗原受体T（LIGHT CAR-T）细胞不仅表现出增强的细胞毒性和细胞因子产生，而且还通过周围细胞改善了CCL19和CCL21的表达。并且LIGHT CAR-T细胞的上清液以旁分泌方式促进T细胞迁移。此外，与传统CAR-T细胞相比，LIGHT CAR-T细胞在免疫缺陷的NSG小鼠中显示出卓越的抗肿瘤疗效和改善的浸润。因此，在C57BL/6同基因肿瘤小鼠模型中，鼠源LIGHT-OT-1 T细胞使肿瘤血管正常化并增强肿瘤内淋巴结构，这意味着LIGHT CAR-T在临床应用中的潜力。综上所述，我们的数据揭示了一种直接的策略，即通过LIGHT表达重定向TLSs来优化CAR-T细胞的运输和细胞毒性，这在扩大和优化CAR-T疗法在实体瘤中的应用方面具有巨大潜力。
