Vista Inhibitors As Emerging Therapeutic Approach in Clinical Trials

Release Date: 31-Jan-2023

With the evolution of clinical research for the identification of more effective treatment methods for cancer, many new methods were introduced into clinical and preclinical trials and are now being used in clinical settings. Among these, immune checkpoint inhibition has emerged as one of the most progressive field and vast number immune checkpoint protein inhibitors have now entered the market. Regardless, the search for more immune checkpoint proteins has not stopped and as a result, newer proteins such as TIM3, LAG-3 and others have been discovered in the last couple of decades. The VISTA protein is one such immune checkpoint which has been slowly gathering attention because of its complicated and controversial influence of on immunity during cancer.


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The V-domain immunoglobulin suppressor of T cell activation protein, often known as VISTA, is a member of the membrane protein B7 family, which also includes the membrane proteins PD-L1, PDL-2, and CD276. It has an IgV domain, a stalk, a transmembrane domain, and a cytoplasmic tail, and it weighs about 30 kDa. VISTA, also known as B7-H5, is highly expressed in hematopoietic tissues, including the bone marrow and spleen, and has been found to express less strongly in non-hematopoietic tissues. Although little is currently known about the protein's roles within the immune system, investigations have shown that they act as both a ligand on antigen-expressing cells and a receptor on T cells. The bulk of studies done so far have described how VISTA suppresses immunological function, but the precise mechanism is still unknown. There have so far been explanations of three binding partners of VISTA. It has been demonstrated that binding to VSIG3 and PSGL-1 results in immunosuppressive effects. Researchers have also discovered another ligand called VSIG8, but they have not yet been able to confirm it. The protein has so been examined as a target for cancer immunotherapy due to its suppression of the immune system.


Investigators have identified a rise in VISTA-expressive white blood cells in the majority of melanoma patients. In patients with colon cancer, a high expression of VISTA has been linked to poor survival. It was also proposed that patients with pancreatic cancer may have immune evasion of pancreatic adenocarcinoma as a result of VISTA signal reduction. When compared to their wild-type counterparts, VISTA knockout mice were found to have high grade hepatitis.  Liu et al. studied chronic inflammation and T cell activation in a single KO mouse model (VISTA and PD-1) and in a double VISTA/PD-1 KO mice model in order to better understand the potential synergism between VISTA and PD-1. They proved that the VISTA pathway and the PD-1 pathway are complementary in their ability to regulate T-cell activation. The administration of the anti-PD-1H monoclonal antibody (mAb) MH5A reduced almost all animal deaths in graft-versus-host disease (GVHD) mouse models.


Since VISTA may rewire the biology of macrophages, it is not just T cell regulation that VISTA regulates that plays a function in controlling inflammation. The lowering of important pro-inflammatory mediators of endotoxin shock was shown by in vitro tests to be caused by an anti-VISTA monoclonal antibody, confirming the idea that VISTA is a negative checkpoint regulator that causes tolerance and anti-inflammatory programmes in macrophages. The failure of VISTA-directed Ig to suppress Th1 and Th17 was reported by a group of researchers who explored the role of VISTA in activating T cells in giant cell arteritis. This failure was likely caused by the lower expression of VISTA on these cells.


The cognate receptor for VISTA and the mechanism by which VISTA controls T cell activation are both poorly understood. But it is understood that VISTA controls T cell activation in both intrinsic and extrinsic ways. It has been implicated in the development both cancer and autoimmune diseases and needs further study if medication against the protein need to developed.



Neeraj Chawla

Kuick research

Research Head


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