Programmed cell death protein 1 and Lymphocyte activation gene 3 protein (PD-1/LAG-3)

Programmed cell death protein 1 (PD-1) and Lymphocyte activation gene 3 protein (LAG-3) are distinct inhibitory receptors co-expressed on the surface of exhausted T cells, particularly within the tumor microenvironment (Andrews, L. P., et al., 2017). While PD-1 primarily limits T cell activity during the effector phase by interacting with PD-L1/2, LAG-3 negatively regulates T cell activation and proliferation by binding to MHC class II molecules (Grosso, J. F., et al., 2007). Co-engagement of these two receptors on the same T cell leads to a state of profound immune suppression and exhaustion, which tumors exploit to evade immune surveillance (Pardoll, D. M., 2012). Therapeutic strategies targeting both pathways simultaneously, such as the combination of nivolumab and relatlimab or bispecific antibodies like tebotelimab, aim to synergistically restore T cell effector functions (Tawbi, H. A., et al., 2022). This dual blockade has demonstrated superior clinical efficacy in treating advanced malignancies, such as melanoma, compared to PD-1 inhibition alone (FDA, 2022). However, the intensified immune activation associated with dual targeting can increase the risk of immune-related adverse events (Tawbi, H. A., et al., 2022). Biomarkers such as LAG-3 expression on tumor-infiltrating lymphocytes are currently used to help identify patients most likely to benefit from this co-engagement strategy (Lipson, E. J., et al., 2022).

Other names

PD-1/LAG-3 dual blockadePD-1 and LAG-3 co-inhibitionSimultaneous PD-1 and LAG-3 targetingPDCD1 and LAG3 co-expressionPD-1 and LAG-3 co-engagement on the same T cell

Simultaneous blockade of PD-1 and LAG-3 inhibitory pathways to reverse T cell exhaustion and enhance anti-tumor immune responses (Andrews, L. P., et al., 2017; Tawbi, H. A., et al., 2022).