Engineered triple inhibitory receptor resistance improves anti-tumor CAR-T cell performance via CD56

Fan Zou, Lijuan Lu, Jun Liu, Baijin Xia, Wanying Zhang, Qifei Hu, Weiwei Liu, Yiwen Zhang, Yingtong Lin, Shuliang Jing, Mei Huang, Bifen Huang, Bingfeng Liu () and Hui Zhang ()
Additional contact information
Fan Zou: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University
Lijuan Lu: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University
Jun Liu: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University
Baijin Xia: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University
Wanying Zhang: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University
Qifei Hu: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University
Weiwei Liu: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University
Yiwen Zhang: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University
Yingtong Lin: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University
Shuliang Jing: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University
Mei Huang: Qianyang Biomedical Research Institute
Bifen Huang: Qianyang Biomedical Research Institute
Bingfeng Liu: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University
Hui Zhang: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract The inhibitory receptors PD-1, Tim-3, and Lag-3 are highly expressed on tumor-infiltrating lymphocytes and compromise their antitumor activity. For efficient cancer immunotherapy, it is important to prevent chimeric antigen receptor T (CAR-T)-cell exhaustion. Here we downregulate these three checkpoint receptors simultaneously on CAR-T cells and that show the resulting PTL-CAR-T cells undergo epigenetic modifications and better control tumor growth. Furthermore, we unexpectedly find increased tumor infiltration by PTL-CAR-T cells and their clustering between the living and necrotic tumor tissue. Mechanistically, PTL-CAR-T cells upregulate CD56 (NCAM), which is essential for their effector function. The homophilic interaction between intercellular CD56 molecules correlates with enhanced infiltration of CAR-T cells, increased secretion of interferon-γ, and the prolonged survival of CAR-T cells. Ectopically expressed CD56 promotes CAR-T cell survival and antitumor response. Our findings demonstrate that genetic blockade of three checkpoint inhibitory receptors and the resulting high expression of CD56 on CAR-T cells enhances the inhibition of tumor growth.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/s41467-019-11893-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11893-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-11893-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().