VISTA: A Mediator of Quiescence and a Promising Target in Cancer Immunotherapy

V-domain Ig suppressor of T cell activation (VISTA) is a B7 family member that maintains T cell and myeloid quiescence and is a promising target for combination cancer immunotherapy. During inflammatory challenges, VISTA activity reprograms macrophages towards reduced production of proinflammatory cytokines and increased production of interleukin (IL)-10 and other anti-inflammatory mediators. The interaction of VISTA with its ligands is regulated by pH, and the acidic pH ~6.0 in the tumor microenvironment (TME) facilitates VISTA binding to P-selectin glycoprotein ligand 1 (PSGL-1). Targeting intratumoral pH might be a way to reduce the immunoinhibitory activity of the VISTA pathway and enhance antitumor immune responses. We review differences among VISTA therapeutics under development as candidate immunotherapies, focusing on VISTA binding partners and the unique structural features of this interaction. V-domain Ig suppressor of T cell activation (VISTA) binds to V-set and Ig domain-containing 3 (VSIG3) and P-selectin glycoprotein ligand 1 (PSGL-1) ligands, and signaling may be bidirectional.VISTA binds to PSGL-1 at acidic pH, such as in the tumor microenvironment (TME), but not at physiological pH.VISTA activity imposes quiescence on mammalian myeloid and naïve T cells, and inhibits T cell activation and cytokine production. It can promote peripheral tolerance via enhanced activation-induced T cell death.VISTA is particularly upregulated on myeloid-derived suppressor cells (MDSCs) via hypoxia, and can contribute to the immunoinhibitory functions of myeloid cells by reducing Toll-like receptor (TLR) signaling and cell migration, as well as by reprogramming myeloid cells towards reduced production of the proinflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-12, and increased production of IL-10 and other anti-inflammatory mediators.Antagonistic VISTA antibodies are in clinical development for treating some cancers; drugs that target the acidity of the TME might reduce immunoinhibitory activity in acidic niches and combine well with VISTA or checkpoint blockade therapies.