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Int J Biol Sci 2023; 19(15):4948-4966. doi:10.7150/ijbs.86632 This issue Cite

Research Paper

Enhanced tumor immunotherapy by polyfunctional CD19-CAR T cells engineered to secrete anti-CD47 single-chain variable fragment

Yingqi Qiu1*, Peiyun Liao1*, Hao Wang1*, Jianyu Chen1, Yuxing Hu1, Rong Hu1, Honghao Zhang1, Zhongwei Li1, Manxiong Cao1, Yulu Yang1, Meifang Li1, Xiaoling Xie1✉, Yuhua Li1,2✉

1. Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510280, P. R. China.
2. Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, Guangdong, 510005, P. R. China.
* These authors contribute equally to this work.

✉ Corresponding authors: Yuhua Li, Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China, 510280; Phone and fax numbers: 86-020-62782316; E-mail: liyuhua1974com; Xiaoling Xie, Department of Hema More

Citation:
Qiu Y, Liao P, Wang H, Chen J, Hu Y, Hu R, Zhang H, Li Z, Cao M, Yang Y, Li M, Xie X, Li Y. Enhanced tumor immunotherapy by polyfunctional CD19-CAR T cells engineered to secrete anti-CD47 single-chain variable fragment. Int J Biol Sci 2023; 19(15):4948-4966. doi:10.7150/ijbs.86632. https://www.ijbs.com/v19p4948.htm
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Abstract

Graphic abstract

A high recurrence rate of non-Hodgkin's lymphoma (NHL) following chimeric antigen receptor T (CAR T) cell treatment remains a bottleneck, and immunosuppressive tumor microenvironment (TME) compromising CAR T cell efficacy in NHL is the primary cause of relapse. Accordingly, modifying the structure of CAR T cells to attenuate the inhibitory effect of TME thus reducing recurrence rate is a valuable research topic. CD47 has been proved to be a promising therapeutic target and is crucial in regulating macrophage function. Herein, we engineered CD19-CAR T cells to secrete an anti-CD47 single-chain variable fragment (scFv) and validated their function in enhancing antitumor efficacy, regulating T cells differentiation, modifying phagocytosis and polarization of macrophages by in vitro and in vivo researches. The efficacy was analogous or preferable to the combination of CAR T cells and CD47 antibody. Of note, anti-CD47 scFv secreting CAR T cells exert a more potent immune response following specific antigen stimulation compared with parental CAR T cells, characterized by more efficient degranulation and cytokine production with polyfunctionality. Furthermore, locally delivering anti-CD47 by CAR T cells potentially limits toxicities relevant to systemic antibody treatment. Collectively, our research provides a more effective and safer CAR T cell transformation method for enhancing tumor immunotherapy.

Keywords: Chimeric antigen receptor T cell, Non-Hodgkin's lymphoma, CD47, T cell polyfunctionality, macrophage

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APA
Qiu, Y., Liao, P., Wang, H., Chen, J., Hu, Y., Hu, R., Zhang, H., Li, Z., Cao, M., Yang, Y., Li, M., Xie, X., Li, Y. (2023). Enhanced tumor immunotherapy by polyfunctional CD19-CAR T cells engineered to secrete anti-CD47 single-chain variable fragment. International Journal of Biological Sciences, 19(15), 4948-4966. https://doi.org/10.7150/ijbs.86632.

ACS
Qiu, Y.; Liao, P.; Wang, H.; Chen, J.; Hu, Y.; Hu, R.; Zhang, H.; Li, Z.; Cao, M.; Yang, Y.; Li, M.; Xie, X.; Li, Y. Enhanced tumor immunotherapy by polyfunctional CD19-CAR T cells engineered to secrete anti-CD47 single-chain variable fragment. Int. J. Biol. Sci. 2023, 19 (15), 4948-4966. DOI: 10.7150/ijbs.86632.

NLM
Qiu Y, Liao P, Wang H, Chen J, Hu Y, Hu R, Zhang H, Li Z, Cao M, Yang Y, Li M, Xie X, Li Y. Enhanced tumor immunotherapy by polyfunctional CD19-CAR T cells engineered to secrete anti-CD47 single-chain variable fragment. Int J Biol Sci 2023; 19(15):4948-4966. doi:10.7150/ijbs.86632. https://www.ijbs.com/v19p4948.htm

CSE
Qiu Y, Liao P, Wang H, Chen J, Hu Y, Hu R, Zhang H, Li Z, Cao M, Yang Y, Li M, Xie X, Li Y. 2023. Enhanced tumor immunotherapy by polyfunctional CD19-CAR T cells engineered to secrete anti-CD47 single-chain variable fragment. Int J Biol Sci. 19(15):4948-4966.

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