Immune checkpoint protein–protein interfaces

Immune checkpoint protein-protein interfaces (PPIs) are the physical contact surfaces between regulatory receptors on immune cells and their corresponding ligands on antigen-presenting cells or tumor cells [Pardoll, 2012, Nature Reviews Cancer]. These interfaces facilitate the transmission of inhibitory or stimulatory signals that maintain self-tolerance and modulate the duration and intensity of immune responses [Sharma & Allison, 2015, Science]. In the context of oncology, many tumors exploit inhibitory PPIs, such as the PD-1/PD-L1 or CTLA-4/B7-1/2 axes, to evade detection and destruction by the immune system [Ribas & Wolchok, 2018, Science]. Therapeutic intervention typically involves the use of monoclonal antibodies or small molecules designed to sterically hinder these interfaces, thereby "releasing the brakes" on the immune system to allow for an effective anti-tumor response [Pardoll, 2012, Nature Reviews Cancer]. Beyond cancer, these interfaces are also targets for treating autoimmune diseases, where the goal is often to enhance inhibitory signaling to suppress overactive immune responses [Sharma & Allison, 2015, Science]. Understanding the structural biology of these interfaces is crucial for the development of next-generation immunotherapies with improved specificity and reduced toxicity [Ribas & Wolchok, 2018, Science]. Current research is expanding to target novel interfaces like TIGIT/PVR and LAG-3/MHC-II to overcome resistance to first-generation inhibitors [Ribas & Wolchok, 2018, Science].

Other names

Immune checkpoint axesCheckpoint receptor-ligand interfacesImmune checkpoint PPIsCo-inhibitory and co-stimulatory pathways

Competitive inhibition of protein-protein interactions to block inhibitory signaling (e.g., PD-1/PD-L1) or enhance co-stimulatory signaling in immune cells [Pardoll, 2012, Nature Reviews Cancer; Sharma & Allison, 2015, Science].