Programmed cell death protein 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) (PD-1/BTLA)

Programmed cell death protein 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) are key inhibitory receptors, or immune checkpoints, expressed on T cells and other immune cells (UniProt Q15116, Q7Z6A9). PD-1 primarily interacts with its ligands PD-L1 and PD-L2 to suppress T-cell activation, while BTLA interacts with Herpesvirus entry mediator (HVEM) to provide a distinct inhibitory signal (PubMed: 16239594). In many cancers, these pathways are co-opted to suppress the host immune response, leading to T-cell exhaustion and tumor progression. Targeting both PD-1 and BTLA pathways simultaneously is a therapeutic strategy designed to overcome resistance to single-agent checkpoint inhibitors (Journal of Hematology & Oncology, 2021). By blocking both signaling cascades, these therapies aim to synergistically restore the effector function of tumor-specific T cells and improve clinical outcomes in patients with advanced malignancies. Current clinical candidates include the BTLA inhibitor tifcemalimab used in combination with the PD-1 inhibitor toripalimab, as well as bispecific antibodies designed to hit both targets (NCT04137900).

Other names

PDCD1 and BTLACD279 and CD272PD-1/BTLA dual checkpointPD-1/BTLA axis

Dual blockade of the PD-1 and BTLA inhibitory pathways to synergistically enhance T-cell activation and anti-tumor immune responses (PubMed: 34154615).