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

• Published in: Nature communications 2022-10, Vol.13 (1), p.6051-6051, Article 6051
• Main Authors: Qin, Le, Cui, Yuanbin, Yuan, Tingjie, Chen, Dongmei, Zhao, Ruocong, Li, Shanglin, Jiang, Zhiwu, Wu, Qiting, Long, Youguo, Wang, Suna, Tang, Zhaoyang, Pan, Huixia, Li, Xiaoping, Wei, Wei, Yang, Jie, Luo, Xuequn, Zhang, Zhenfeng, Tang, Qiannan, Liu, Pentao, Weinkove, Robert, Yao, Yao, Qin, Dajiang, Thiery, Jean Paul, Li, Peng
• Format: Article
• Language: English
• Subjects: 13/1; 13/21; 13/31; 14/19; 38/91; 42/109; 631/250/1619/554; 631/250/2152; 631/250/251/1574; 631/67/1059/2325; 64/60; Anticancer properties; Antigens; Antitumor activity; B7-H1 Antigen - genetics; CD19 antigen; CD27 antigen; CD28 antigen; CD28 Antigens - genetics; CD3 antigen; CD70 antigen; Cell differentiation; Cell Line, Tumor; Chimeric antigen receptors; Confocal microscopy; Cytokines; Cytokines - metabolism; Differentiation; Effectiveness; Gene sequencing; Humanities and Social Sciences; Immunological memory; Lymphocytes; Lymphocytes T; Memory cells; multidisciplinary; PD-L1 protein; Receptors; Receptors, Antigen, T-Cell - metabolism; Receptors, Chimeric Antigen - genetics; RNA; Science; Science (multidisciplinary); Sequence analysis; Target recognition; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33793-w

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. Co-expression of PD-L1-specific chimeric switch receptors (CSRs) improves the antitumor effects of chimeric antigen receptor (CAR) T cells. Here, CSRs are shown to promote the differentiation of mesothelin-targeting CAR T cells into central memory-like cells and improve their efficacy.