Structure and functional binding epitopes of VISTA

V-domain Ig Suppressor of T-cell Activation (VISTA) is an immune checkpoint protein involved in the regulation of T cell activity. Checkpoint proteins are overexpressed by cancer cells or surrounding immune cells and prevent anti-tumor activity by co-opting natural regulation mechanisms to escape immune clearance. Compared to healthy tissues, VISTA is upregulated on tumor infiltrating leukocytes, including high expression on myeloid-derived suppressor cells (MDSCs). Through VISTA signaling, these inhibitory immune cells prevent effective antigen presentation and indirectly promote tumor growth. VISTA is implicated in a number of human cancers including skin (melanoma), prostate, colon, pancreatic, ovarian, endome­trial, and non-small cell lung. VISTA is a known member of the B7 protein family but the mechanism of action is still unclear as VISTA has been shown to function as both a ligand1,2 and a receptor3.  In the model of VISTA as a receptor, the proposed ligand of interaction is V-set and immunoglobulin domain containing 3 (VSIG3)4,5.

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Image: Structure of human VISTA with extended C-C’ loop (blue), mapped VSTB/VSIG3 binding epitope (red), and disulfide bonds (yellow).