In vitro and in vivo studies of VISTA: a B7 family immune checkpoint receptor

Abstract

Immunotherapy has become an established pillar of cancer treatment, in large part owing to the success of blocking the programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD- L1) immune checkpoint pathway. V-domain Ig suppressor of T cell activation (VISTA) is a B7 family member that maintains T cell and myeloid quiescence and is a promising target for combination cancer immunotherapy. Previous studies have shown during inflammatory challenges, VISTA activity reprograms macrophages towards reduced production of proinflammatory cytokines and increased production of interleukin (IL)-10 and other anti-inflammatory mediators. The interaction of VISTA with its ligands is regulated by pH, and the acidic pH ~6.0 in the tumor microenvironment (TME) facilitates VISTA binding to P-selectin glycoprotein ligand 1 (PSGL-1). In this study, the binding of human VISTA to human PSGL-1 is confirmed by cell-to-cell binding assay but the interaction in mice is shown to be more intricate. Moreover, examination of mouse VISTA and mouse PSGL-1 expression in healthy mice and various tumor models (RENCA, 4T1, MC38-OVA, and B16-OVA) help identify a unique myeloid population, which is enriched in tumor tissues and spleen in tumor-bearing mice. The abundance of VISTA+ PSGL-1+ immune cells in tumor-bearing mice leads to the question of whether VISTA and PSGL-1 mediate non-redundant immunosuppressive pathways?