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

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.

Targeting PD-L1 in solid cancer with myeloid cells expressing a CAR-like immune receptor

“…As a chimeric receptor, CARIR is akin to the previously described PD-1-CD28 fusion receptor or PD-L1-specific chimeric switch receptor (CSR) for T cells ( 20 – 22 ). The common feature of these chimeric receptors is that the extracellular domain is derived from the immune checkpoint molecule PD-1.…”

“…However, the intracellular domain usage and the functional utility of these chimeric receptors differ. The only cytosolic domain of PD-1-CD28 fusion receptor or PD-L1-specific CSR is derived from the costimulatory molecule CD28, and the purpose of expressing these chimeric receptors is to enhance the functionality of tumor-specific TCR-T or CAR-T cells ( 20 – 22 ). In the present study, however, the purpose of the CARIR is to direct macrophages to recognize and attack PD-L1 + solid cancer cells and reprogram immunosuppressive TME.…”

Toward the clinical development of synthetic immunity to cancer

“…These receptors bind to PD-L1, which is highly expressed in suppressive tumor microenvironments, and boost activating T-cell signaling rather than dampen it. 134,135 Switch receptors are modular with their inputs and outputs, and multiple designs have been developed targeting other ligands such as Fas, fusing FasR to 4-1BB intracellular signaling domains, 136 or targeting immunosuppressive cytokines such as the GM-CSF/IL-18 switch receptors, 137 or even a TGFβ/IL-7. 138 In cases where these enhancements can conform to the cargo capacity of cell therapies, they equip the graft with additional capabilities to overcome multiple suppressive mechanisms.…”

“…One example of this is the PD‐1/CD28 switch receptor, which fuses the PD‐1 receptor extracellular region to a CD28 costimulatory receptor intracellular domain. These receptors bind to PD‐L1, which is highly expressed in suppressive tumor microenvironments, and boost activating T‐cell signaling rather than dampen it 134,135 . Switch receptors are modular with their inputs and outputs, and multiple designs have been developed targeting other ligands such as Fas, fusing FasR to 4‐1BB intracellular signaling domains, 136 or targeting immunosuppressive cytokines such as the GM‐CSF/IL‐18 switch receptors, 137 or even a TGFβ/IL‐7 138 .…”

CAR designs for solid tumors: overcoming hurdles and paving the way for effective immunotherapy

“…Another study elucidated that coexpression of CSR specific for PD-L1 enhances the antitumor effects of anti-mesothelin CAR-T (CARMz) both in vitro and in vivo . Interestingly, the coexpression of CSR specific for PD-L1 promotes the differentiation of CARMz T cells into central memory-like T cells, as evidenced by the upregulation of Th1-related genes and downregulation of Th2-associated cytokines mediated through the CD70-CD27 axis (Qin et al 2022 ). These innovative approaches show promise for overcoming CAR-T exhaustion and maximizing their therapeutic potential.…”