V-domain Ig suppressor of T cell activation (VISTA) is a type I transmembrane protein that functions as an immune checkpoint and is encoded by the VSIR gene. [5] [6] [7]
V-domain Ig suppressor of T cell activation (VISTA) is a type I transmembrane protein that functions as an immune checkpoint and is encoded by the VSIR gene. [5] [6] [7]
VISTA is approximately 50 kDa and belongs to the immunoglobulin superfamily and has one IgV domain. [8] [5]
VISTA is part of the B7 family, is primarily expressed in white blood cells and its transcription is partially controlled by p53. [8] [9] There is evidence that VISTA can act as a ligand that engages an inhibitory receptor LRIG1 on T cells and impairs T cell activation and function [10] Another binding partner for VISTA is PSGL-1, which binds VISTA only under acidic conditions (pH<6.5). [11] . VISTA expressed on T cells also intrinsically suppresses T cell activation, likely by engaging other inhibitory receptors on the same cell [12] . Aside from T cells, VISTA is highly expressed on macrophages and myeloid-derived suppressor cells (MDSCs) and regulates their differentiation and function [13] . [14] . Similarly, VISTA and TIM-3 may co-exist on macrophages infiltrating different human and mouse tumours where they can co-regulate immunotherapy resistance. [15]
VISTA is expressed at high levels in tumor-infiltrating lymphocytes, such as myeloid-derived suppressor cells and regulatory T cells, and its blockade with an antibody results in delayed tumor growth in mouse models of melanoma [16] and squamous cell carcinoma. [17] It is also up-regulated in tumour-associated macrophages in various malignancies, including melanoma, especially in immunotherapy-resistant human context. [15] VISTA cooperates with another immune checkpoint receptor PD-1 in modulating anti-tumor immunity and autoimmunity [18] .
Monocytes from HIV-infected patients produce higher levels of VISTA compared to uninfected individuals. The increased VISTA levels correlated with an increase in immune activation and a decrease in CD4-positive T cells. [19]
There are several ongoing cancer immunotherapy clinical trials for a monoclonal antibodies targeting VISTA in advanced cancer. [20] Preliminary results of the phase I clinical trials show good safety tolerance and anti-cancer activity in patients with advanced tumours. [21] . One new approach uses an antibody (SNS-101) that only binds to VISTA when the multiple histidine residues of VISTA are protonated inside acid tumors. This approach improves the pharmacokinetics of the anti-VISTA antibody. [22] Another ongoing clinical trial involves a small molecule that antagonizes the programmed death-ligands 1 and 2 (PD-L1 and PD-L2), and VISTA pathways in patients with advanced solid tumors or lymphomas. [23]