B- and T-lymphocyte attenuator–Herpesvirus entry mediator axis (BTLA–HVEM axis) (BTLA–HVEM axis)

The B- and T-lymphocyte attenuator (BTLA) and Herpesvirus entry mediator (HVEM) axis is a critical immune checkpoint pathway that regulates lymphocyte activation and homeostasis (PMID: 31435310). BTLA, a member of the immunoglobulin superfamily (UniProt: Q7Z6A9), contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and is expressed on various immune cells, including T and B cells. Its ligand, HVEM, is a member of the tumor necrosis factor receptor (TNFR) superfamily (UniProt: Q92956), making this interaction unique as it bridges two different protein families (PMID: 15690044). When BTLA binds to HVEM, it delivers a potent inhibitory signal to T cells, similar to the PD-1/PD-L1 pathway, which helps prevent overactive immune responses but can be exploited by tumors to evade immune surveillance (PMID: 33614316). In many cancers, such as melanoma and lymphoma, the BTLA–HVEM axis is upregulated, leading to T-cell exhaustion and tumor progression. Therapeutic strategies currently focus on using monoclonal antibodies, such as tifcemalimab (JS006), to block this interaction and reinvigorate the anti-tumor immune response (NCT04137900).

Other names

CD272–TNFRSF14 axisBTLA–TNFRSF14 interactionB- and T-lymphocyte attenuator–Herpesvirus entry mediator pathwayLIGHTR–BTLA axis

Monoclonal antibodies targeting this axis typically block the inhibitory interaction between BTLA and HVEM, thereby restoring T-cell activation and enhancing anti-tumor immune responses (PMID: 33614316).