CXCR2‐modified CAR‐T cells have enhanced trafficking ability that improves treatment of hepatocellular carcinoma. Issue 5 (10th February 2020)

• Record Type: Journal Article
• Authors: Liu, Guangna; Rui, Wei; Zheng, Hongli; Huang, Daosheng; Yu, Fei; Zhang, Yuewei; Dong, Jiahong; Zhao, Xueqiang; Lin, Xin
• Is Part Of: European journal of immunology. Volume 50:Issue 5(2020)
• Page Start: 712
• Page End: 724
• Publication Date: 2020-02-10
• Subjects: Immunotherapy -- CAR‐T -- Chemokine -- CXCR2; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201948457
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: 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. Abstract : Since several chemokine ligands of CXCR2 are enriched in hepatocellular carcinoma, through introducing CXCR2 into CAR‐T cells targeting glypican‐3, we substantiate that such self‐driving CAR‐T cells possess enhanced trafficking ability and better anti‐tumor effect. These results provide rational strategy to improve efficacy of CAR‐T cells in treating solid tumors.