Immune checkpoints. A, Cytotoxic CTLA-4 is expressed on T cells after activation and competes with the co-stimulatory T-cell CD28 receptor for CD80/86 expressed by APCs, providing an inhibitory signal to the T cell. B, PD-1 receptor is up-regulated on activated T cells and subsequently binds to one of its ligands, PD-L1 or PD-L2, which are commonly expressed on tumor cells, providing an inhibitory signal to the T cell. APC, antigen-presenting cell; MHC, major histocompatibility; TCR, T-cell receptor; CTLA-4, cytotoxic T-lymphocyte antigen-4; PD-L1/L2, programmed death ligand-1/ligand-2; PD-1, programmed death-1. Adapted with permission from: Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252–264.