Structure and Functional Binding Epitope of V-domain Ig Suppressor of T Cell Activation

Abstract

Summary: V-domain immunoglobulin (Ig) suppressor of T cell activation (VISTA) is an immune checkpoint protein that inhibits the T cell response against cancer. Similar to PD-1 and CTLA-4, a blockade of VISTA promotes tumor clearance by the immune system. Here, we report a 1.85 Å crystal structure of the elusive human VISTA extracellular domain, whose lack of homology necessitated a combinatorial MR-Rosetta approach for structure determination. We highlight features that make the VISTA immunoglobulin variable (IgV)-like fold unique among B7 family members, including two additional disulfide bonds and an extended loop region with an attached helix that we show forms a contiguous binding epitope for a clinically relevant anti-VISTA antibody. We propose an overlap of this antibody-binding region with the binding epitope for V-set and Ig domain containing 3 (VSIG3), a purported functional binding partner of VISTA. The structure and functional epitope presented here will help guide future drug development efforts against this important checkpoint target. : Using a combinatorial MR-Rosetta approach, Mehta et al. solve the crystal structure of human V-domain immunoglobulin (Ig) suppressor of T cell activation (VISTA), an important checkpoint protein in cancer immunotherapy. The authors use yeast display to map the epitope of a clinical anti-VISTA antibody and demonstrate its overlap to the VISTA/V-set and Ig domain containing 3 (VSIG3) binding interface. Keywords: VISTA, PD-1H, B7-H5, cancer immunotherapy, checkpoint inhibitor, high resolution crystal structure, VSIG3, IGSF11, yeast display, epitope mapping