immune checkpoint pathway
Any of a plethora of inhibitory pathways in the immune system which is required for maintaining self-tolerance and modulating the duration and degree of normal (physiologic) immune responses in peripheral tissues, as a way of minimising collateral tissue damage.
Tumours may circumvent immune-checkpoint pathways as a mechanism of resistance, especially against tumour antigen-specific T cells. Because many immune checkpoints are initiated by ligand-receptor interactions, they can be blocked by antibodies or modulated by recombinant forms of ligands or receptors.
Cytotoxic T-lymphocyte-associated antigen 4–CTLA4 antibodies were the first FDA-approved member of this class of immunotherapeutics; other immune checkpoint block targets–e.g., programmed cell death protein 1–are in the pipeline.
Caption for image Known signaling pathways of selected checkpoint molecules and current therapeutics. Upon binding B7-1 or B7-2, CTLA-4 recruits the phosphatases SHP2 and PP2A via the YVKM motif in its cytoplasmic domain. SHP2 recruitment results in attenuation of TCR signaling by dephosphorylating the CD3ζ chain. PP2A recruitment results in downstream dephosphorylation of AKT, further dampening the T-cell activation pathway. PD-1 ligation by PD-L1 or PD-L2 also recruits SHP2 to the ITSM domain, resulting in membrane proximal decreases in TCR signaling. LAG-3 signaling is dependent on interaction with its ligand, MHC II, as well as its intracellular KIEELE domain. TIM-3 binds to Galectin-9, as well as other ligands. In the absence of ligand binding, TIM-3 is associated with Bat3, protecting the cell from TIM-3–mediated inhibition and allowing for greater activation. However, once TIM-3 binds to Galectin-9, Y265 is phosphorylated and the interaction with Bat3 is disrupted, allowing TIM-3 to deliver inhibitory signals to the T cell. BTLA and CD160 bind to herpes virus entry mediator. BTLA contains an intracellular ITIM domain that may be important in signaling. 2B4 has four intracellular ITSM domains and binds to CD48, but further signaling mechanisms are poorly understood. Ig domains are depicted in orange, mucin domains in green, cysteine-rich domains in brown, and GPI anchors as bolded black lines. Current therapeutics to block checkpoint-signaling molecules include both monoclonal antibodies and Ig fusion proteins: (i) anti-CTLA-4: ipilimumab (BMS-734016), tremelimumab (CP-675206), (ii) anti-PD-1: nivolumab (BMS-936558, MDX1106), lambrolizumab (MK-3475), CT-011 (iii) anti PD-L1: BMS-936559 (MDX1105), MEDI4736, (iv) PD-L2 Ig: AMP224, and (v) LAG-3 Ig: IMP321.
Reference Nat Rev Cancer. 2012 Mar 22;12(4):252-64