Co-expression of a PD-L1-specific chimeric switch receptor augments the efficacy and persistence of CAR T cells via the CD70-CD27 axis

Le Qin, Yuanbin Cui, Tingjie Yuan, Dongmei Chen, Ruocong Zhao, Shanglin Li, Zhiwu Jiang, Qiting Wu, Youguo Long, Suna Wang, Zhaoyang Tang, Huixia Pan, Xiaoping Li, Wei Wei, Jie Yang, Xuequn Luo, Zhenfeng Zhang, Qiannan Tang, Pentao Liu, Robert Weinkove, Yao Yao, Dajiang Qin, Jean Paul Thiery () and Peng Li ()
Additional contact information
Le Qin: Chinese Academy of Sciences
Yuanbin Cui: Chinese Academy of Sciences
Tingjie Yuan: The Fifth Affiliated Hospital of Guangzhou Medical University
Dongmei Chen: Chinese Academy of Sciences
Ruocong Zhao: Chinese Academy of Sciences
Shanglin Li: Chinese Academy of Sciences
Zhiwu Jiang: Chinese Academy of Sciences
Qiting Wu: Chinese Academy of Sciences
Youguo Long: Chinese Academy of Sciences
Suna Wang: Chinese Academy of Sciences
Zhaoyang Tang: Guangdong Zhaotai InVivo Biomedicine Co. Ltd
Huixia Pan: Guangdong Zhaotai InVivo Biomedicine Co. Ltd
Xiaoping Li: the Third Affiliated Hospital of Sun Yat-sen University
Wei Wei: Guangdong Cord Blood Bank
Jie Yang: Guangdong Women and Children Hospital, Panyu
Xuequn Luo: Sun Yat-Sen University
Zhenfeng Zhang: the Second Affiliated Hospital of Guangzhou Medical University
Qiannan Tang: The University of Hong Kong
Pentao Liu: The University of Hong Kong
Robert Weinkove: Malaghan Institute of Medical Research
Yao Yao: Chinese Academy of Sciences
Dajiang Qin: The Fifth Affiliated Hospital of Guangzhou Medical University
Jean Paul Thiery: Guangzhou Laboratory
Peng Li: Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Co-expression of chimeric switch receptors (CSRs) specific for PD-L1 improves the antitumor effects of chimeric antigen receptor (CAR) T cells. However, the effects of trans-recognition between CSRs and PD-L1 expressed by activated CAR T cells remain unclear. Here, we design a CSR specific for PD-L1 (CARP), containing the transmembrane and cytoplasmic signaling domains of CD28 but not the CD3 ζ chain. We show that CARP T cells enhance the antitumor activity of anti-mesothelin CAR (CARMz) T cells in vitro and in vivo. In addition, confocal microscopy indicates that PD-L1 molecules on CARMz T cells accumulate at cell-cell contacts with CARP T cells. Using single-cell RNA-sequencing analysis, we reveal that CARP T cells promote CARMz T cells differentiation into central memory-like T cells, upregulate genes related to Th1 cells, and downregulate Th2-associated cytokines through the CD70-CD27 axis. Moreover, these effects are not restricted to PD-L1, as CAR19 T cells expressing anti-CD19 CSR exhibit similar effects on anti-PSCA CAR T cells with truncated CD19 expression. These findings suggest that target trans-recognition by CSRs on CAR T cells may improve the efficacy and persistence of CAR T cells via the CD70-CD27 axis.

Date: 2022
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DOI: 10.1038/s41467-022-33793-w

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