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

Area of Science:

• Immunology
• Transplantation Biology
• Oncology

Background:

• Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by graft-versus-host disease (GVHD).
• T-cell activation drives GVHD, and coinhibitory molecules like VISTA (V-domain immunoglobulin-containing suppressor of T-cell activation) can restrain T-cell activity.
• VISTA expression increases on donor T cells in allo-HSCT recipients, making them susceptible to anti-VISTA antibody-mediated depletion.

Purpose of the Study:

• To investigate the efficacy of anti-VISTA monoclonal antibody (mAb) in preventing lethal acute GVHD.
• To determine the mechanism of anti-VISTA mAb-mediated T-cell depletion and its impact on the graft-versus-lymphoma (GVL) effect.
• To explore the potential clinical translational pathway for using anti-VISTA mAb in allo-HSCT.

Main Methods:

• Utilized multiple animal models of allo-HSCT and GVHD.
• Administered a single dose of anti-VISTA mAb to assess GVHD lethality and T-cell depletion.
• Investigated the role of different cell types and Fc receptor-mediated phagocytosis in T-cell elimination.
• Evaluated the GVL effect in lymphoma challenge models and assessed outcomes in xenogeneic GVHD models.

Main Results:

• A single dose of anti-VISTA mAb prevented acute GVHD lethality in multiple models.
• Anti-VISTA mAb-mediated deletion of alloreactive T cells required targeting a non-T cell type and occurred via Fc receptor-mediated phagocytosis.
• The graft-versus-lymphoma effect was largely retained when anti-VISTA mAb targeted donor T cells, even when unseparated.
• Anti-VISTA mAb reduced donor T-cell expansion and recipient lethality in a xenogeneic GVHD model.

Conclusions:

• Anti-VISTA mAb is a promising strategy for mitigating acute GVHD lethality post-allo-HSCT.
• This approach can preserve the graft-versus-lymphoma effect, crucial for eliminating residual cancer cells.
• Targeting VISTA offers a novel clinical pathway to improve allo-HSCT outcomes by controlling GVHD without compromising anti-tumor immunity.