CXCR2-modified CAR-T cells have enhanced trafficking ability that improves treatment of hepatocellular carcinoma.,European Journal of Immunology

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CXCR2-modified CAR-T cells have enhanced trafficking ability that improves treatment of hepatocellular carcinoma.
European Journal of Immunology ( IF 4.5 ) Pub Date : 2020-02-10 , DOI: 10.1002/eji.201948457
Guangna Liu ₁ , Wei Rui ₁ , Hongli Zheng ₁ , Daosheng Huang ₁ , Fei Yu ₂ , Yuewei Zhang ₂ , Jiahong Dong ₂ , Xueqiang Zhao ₁ , Xin Lin _{1,

3}

Affiliation

Unlike hematological malignancies, solid tumors have proved to be less susceptible to chimeric antigen receptor (CAR)-T cell therapy, which is partially caused by reduced accumulation of therapeutic T cells in tumor site. Since efficient trafficking is the precondition and pivotal step for infused CAR-T cells to exhibit their anti-tumor function, strategies are highly needed to improve the trafficking ability of CAR-T cells for solid tumor treatment. Here, based on natural lymphocyte chemotaxis theory and characteristics of solid tumor microenvironments, we explored the possibility of enhancing CAR-T cell trafficking by using chemokine receptors. Our study found that compared with other chemokines, several CXCR2 ligands showed relatively high expression level in human hepatocellular carcinoma tumor tissues and cell lines. However, both human peripheral T cells and hepatocellular carcinoma tumor infiltrating T cells lacked expression of CXCR2. CXCR2-expressing CAR-T cells exhibited identical cytotoxicity but displayed significantly increased migration ability in vitro. In a xenograft tumor model, we found that expressing CXCR2 in CAR-T cells could significantly accelerate in vivo trafficking and tumor-specific accumulation, and improve anti-tumor effect of these cells.

中文翻译：

CXCR2修饰的CAR-T细胞具有增强的运输能力，从而改善了肝细胞癌的治疗。

与血液系统恶性肿瘤不同，已证明实体瘤对嵌合抗原受体（CAR）-T细胞疗法的敏感性较低，这部分是由于治疗性T细胞在肿瘤部位的积累减少所致。由于有效的运输是输注的CAR-T细胞表现出其抗肿瘤功能的前提和关键步骤，因此迫切需要提高CAR-T细胞用于实体瘤治疗的运输能力的策略。在这里，基于天然淋巴细胞趋化理论和实体瘤微环境的特征，我们探索了使用趋化因子受体增强CAR-T细胞运输的可能性。我们的研究发现，与其他趋化因子相比，几种CXCR2配体在人类肝细胞癌肿瘤组织和细胞系中显示出相对较高的表达水平。然而，人外周T细胞和肝癌浸润性T细胞均缺乏CXCR2的表达。表达CXCR2的CAR-T细胞具有相同的细胞毒性，但在体外的迁移能力却显着提高。在异种移植肿瘤模型中，我们发现在CAR-T细胞中表达CXCR2可以显着加速体内运输和肿瘤特异性积累，并改善这些细胞的抗肿瘤作用。

更新日期：2020-02-10

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