Programmed cell death protein 1, Programmed cell death 1 ligand 1, and Cytotoxic T-lymphocyte protein 4 (PD-1/PD-L1/CTLA-4)

Programmed cell death protein 1 (PD-1), its ligand (PD-L1), and Cytotoxic T-lymphocyte protein 4 (CTLA-4) are critical inhibitory checkpoint molecules that regulate the intensity and duration of immune responses (Pardoll, 2012, Nature Reviews Cancer). PD-1 and CTLA-4 are receptors expressed primarily on T cells, while PD-L1 is often upregulated on the surface of tumor cells and antigen-presenting cells to evade immune detection (Wei et al., 2018, Cell). In the context of oncology, tumors exploit these pathways to suppress T-cell activation and escape surveillance (Hanahan & Weinberg, 2011, Cell). Therapeutic blockade of these proteins using monoclonal antibodies—often referred to as checkpoint inhibitors—restores the ability of the immune system to recognize and destroy cancer cells (Vaddepally et al., 2020, Journal of Clinical Medicine). While highly effective across various malignancies, these therapies can trigger immune-related adverse events (irAEs) due to the systemic loss of self-tolerance (Postow et al., 2018, NEJM).

Other names

CD279CD274CD152B7-H1B7-DCB7-1/B7-2 receptorImmune checkpoints

These targets are inhibited by monoclonal antibodies that disrupt the binding of inhibitory receptors to their ligands. CTLA-4 blockade acts primarily during the priming phase of the immune response in lymph nodes by preventing CTLA-4 from outcompeting the costimulatory receptor CD28 for B7 ligands (Leach et al., 1996, Science). PD-1/PD-L1 blockade acts primarily in the effector phase within the tumor microenvironment, preventing the PD-L1-mediated exhaustion of T cells and allowing them to maintain cytotoxic activity against tumor cells (Ribas & Wolchok, 2018, Science).