B7 family checkpoint regulators in immune regulation and disease

• In the clinic, targeting blocking the CTLA-4 and PD-1 pathway is advantageous in cancer patients.
• Preclinical studies show that B7-H4 and B7-H6 are promising targets in cancer.
• VISTA, a novel B7 inhibitory ligand, maybe a therapeutic target in cancer and autoimmunity.

Fine-tuning the immune response and maintaining tolerance to self-antigens involves a complex network of co-stimulatory and co-inhibitory molecules. The recent FDA approval of ipilimumab, a monoclonal antibody blocking cytotoxic T lymphocyte antigen (CTLA)-4, demonstrates the impact of checkpoint regulators in disease. This is reinforced by ongoing clinical trials targeting not only CTLA-4, but also the programmed death (PD)-1 and B7-H4 pathways in various disease states. Recently, two new B7 family inhibitory ligands, V-domain Ig suppressor of T cell activation (VISTA) and B7-H6 were identified. Here, we review recent understanding of B7 family members and their concerted regulation of the immune response to either self or foreign pathogens. We also discuss clinical developments in targeting these pathways in different disease settings, and introduce VISTA as a putative therapeutic target.