VISTA (V domain-containing immunoglobulin suppressor of T-cell activation), also known as PD-1 homolog (PD-1H), DD1α, Gi24, Dies1, and B7-H5, is a unique inhibitory immune checkpoint molecule of the B7 family. Recently, VSIG3 (V-Set and Immunoglobulin domain containing 3) has been identified as a VISTA ligand that suppresses human T cell activation. For more information on VISTA-involved pathways, please visit the VISTA pathway.
Table.1 Immune checkpoint VISTA.
| Checkpoint receptor | Alternate name | Cell type affected | Ligand | Function of ligand-receptor interaction | Notes |
| VISTA | PD-1H / B7-H5 / Gi24 / Dies1 | Hematopoietic cells | Unknown | Co-inhibition | Preclinical studies with VISTA blockade show promising improvement in antitumor T cell responses and improved survival. |
VISTA is a transmembrane protein with an extracellular IgV domain, a stalk region, a transmembrane segment, and a cytoplasmic tail. Besides the similarities of the IgV domain of VISTA extracellular domain to CD28 and B7 families, structural analysis shows some different VISTA characters from the B7 family, such as (1) no classical immunoreceptor tyrosine-based signaling motifs in the cytoplasmic domain of VISTA; (2) two potential sites for protein kinase C and casein kinase 2 phosphorylation sites in the intracellular tail of VISTA; (3) only a single extracellular IgV-like domain.
VISTA is expressed predominantly on hematopoietic cells with the greatest densities on myeloid cells, including the expression on macrophages, conventional dendritic cells, monocytes. Meanwhile, VISTA expression is at a lower level in T cells and NK cells, while B cells do not express VISTA. Unlike other checkpoints induced at different stages after activation, VISTA is constitutively expressed on these subsets at a steady state. The broad and unique expression pattern implies a crucial homeostatic role in regulating immune system responses and distinguishes VISTA from other immunoregulatory receptors.
VISTA acts as both a ligand and receptor in regulating immune responses based on its expression. On the one hand, VISTA functions as a ligand to negatively regulate T cell activation, proliferation, and cytokine production. On the other hand, VISTA functions as an inhibitory receptor on T cells to suppress their activation. Several studies have shown that the loss of VISTA enhances tumor responses and precipitates autoimmunity. For example, VISTA-deficiency shows to exacerbate diseases, such as lupus, allergic inflammation, and experimental asthma, while VISTA agonists suppress both cutaneous and systemic lupus. This present evidence indicates that VISTA plays a broad role in fine-tuning and establishing a normal response, thereby restraining autoimmunity and excessive damage.
Previous studies have investigated VISTA expression in human cancers such as lung cancer, gastric cancer, and gestational trophoblastic neoplasia. VISTA is a novel immunoregulatory receptor and an emerging target for cancer immunotherapy. VISTA has been indicated to blockade T cell effector functions and synergizes with other immune checkpoint inhibitors such as anti-PD-L1 agents in cancer models in some preclinical studies. Given the significant therapeutic activity in multiple preclinical tumor models, VISTA-specific antagonists have moved forward into the clinic, and two molecules are being tested on early-phase clinical trials.
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