Solving structure-function predicament of VISTA a novel immune checkpoint inhibitor

Recent studies have revealed a negative checkpoint regulator named V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation (VISTA). It has function similar to it’s other B7 family members such as PD1, PD2 and CTLA-4 although presenting very low sequence homology.VISTA is highly expressed on myeloid derived suppressor cells (MDSCs) which are presently potential therapeutic targets for immunotherapy against cancer.

VISTA is a key regulator of T-cell inactivation in Mesothelioma and other types of cancers. There is currently only one confirmed Ligand for VISTA called VSIG-3 but further no information about how it binds or after binding how the complex functions is available. As VISTA is found to be present on both APCs and T cells there could be possibility that it binds to itself or potentially some other ligands as well.

Hence, we are trying to deduce the crystal structure and find the ligands of Vista in order to reveal the binding site and the mechanism of action. To date we have cloned a suitable construct containing the extra-cellular part of the protein which is responsible for binding its ligand on the tumor cell surface and expressed in prokaryotic and eukaryotic cells. At the moment we are still trying to standardize the purification and expression protocols. In future we hope to crystallize and perform binding assays on the purified protein with a possible set of ligands. Studying structure-function of VISTA could provide a platform synthesizing a new drug for Immunotherapy.