T cells expressing a chimeric switch receptor augment the efficacy and persistence of CAR T cells via the CD70-CD27 axis

Here, we designed a CSR specific for PD-L1 (CARP), containing the transmembrane and cytoplasmic signaling domains of CD28 but not CD3 zeta chain. CARP T cells enhanced the antitumor activity of anti-mesothelin CAR (CARMz) T cells in vitro and in vivo. Confocal microscopy shows PD-L1 molecules on CARMz T cells accumulate at cell-cell contacts with CARP T cells. Single-cell RNA-sequencing analysis reveals that CARP T cells promoted CARMz T cells to differentiate into central memory-like T cells, upregulate genes related to Th1 cells, and downregulate Th2-associated cytokines through the CD70-CD27 axis. In addition, these effects were not restricted to a particular antigen like PD-L1, as CAR19 T cells that expressed anti-CD19 CSR exhibited similar effects on anti-PSCA CAR T cells with truncated CD19 expression. Therefore, the trans-recognition between CSR and its antigen on CAR T cells may improve the efficacy and persistence of CAR T cells via the CD70-CD27 axis.