Targeting cell surface VISTA expression on allospecific naïve T cells promotes tolerance

• VISTA mAb targeting in murine acute GvHD leads to profound deletion of allo-specific CD4 T-cells

• Donor T-cell deletion occurs via FcReceptor mediated elimination by phagocytic cells and is incompatible with peri-BMT CNI prophylaxis.

The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be limited by graft-versus-host disease (GVHD). T-cell activation is a key factor in GVHD progression. Costimulatory signals can be counterbalanced by co-inhibitory signals such as the checkpoint molecule VISTA (V-domain Ig-containing suppressor of T-cell activation)/PD-1H that restrains activation and maintains donor T-cell quiescence. A single dose of anti-VISTA mAb prevents acute GVHD lethality in multiple models. Naïve donor T-cells express moderate VISTA levels, which transiently increase in allo-HSCT recipients in association with TCR signaling, leading to heightened susceptibility to anti-VISTA mAb-mediated depletion, in contrast to donor T-cells transferred to syngeneic recipients. Anti-VISTA mAb donor T-cell depletion was compatible with rapamycin but incompatible with peri-transplant tacrolimus GVHD prophylaxis. Targeting VISTA exclusively on host cells or donor CD8+ T-cells was not protective against GVHD lethality. Instead, anti-VISTA mAb mediated deletion of alloreactive donor T-cells depended on targeting a third (non-T) cell type. Further mechanistic studies indicated that donor T-cells concurrently exposed to anti-VISTA mAb in vivo but not preincubated in vitro before adoptive T-cell transfer were eliminated via FcR-mediated phagocytosis. In a lymphoma challenge model, a graft-versus-lymphoma effect was fully retained when anti-human VISTA mAb exclusively targeted donor CD4+ T-cells and delayed but mostly retained when unseparated donor T-cells were infused. In a xenogeneic GVHD model, anti-human VISTA mAb reduced donor T-cell expansion, VISTA T-cell expression levels, and recipient lethality. Together, these data support a novel clinical translational pathway in which acute GVHD lethality can be mitigated without negating the GVL effect.