LAUSR

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for both malignant and nonmalignant hematologic disorders. However, graft-versus-host disease (GvHD) and malignant relapse limit its therapeutic success. We previously demonstrated that blockade of interferon-gamma receptor (IFNGR) signaling in donor T cells resulted in a reduction of GvHD while preserving graft-versus-leukemia (GvL) effects. Nonetheless, the underlying molecular mechanisms remain inconclusive. In this study, we find that S100A9 is a novel GvHD suppressor upregulated when IFNGR is blocked in T cells. Both Ifngr1-/- and S100a9-overexpressing T cells significantly reduce GvHD without compromising GvL, altering donor T cell trafficking to GvHD target organs in our mouse model of allo-HSCT. In addition, in vivo administration of recombinant murine S100A9 proteins prolongs the overall survival of recipient mice. Furthermore, in vivo administration of anti-human IFNGRα neutralizing antibody (αhGR-Nab) significantly upregulates the expression of S100A9 in human T cells and improves GvHD in our mouse model of xenogeneic human PBMC transplantation. Consistent with S100a9-overexpressing T cells in our allo-HSCT model, αhGR-Nab also reduces human T cell trafficking to GvHD target organs. Taken together, S100A9, a downstream molecule suppressed by IFNGR signaling, functions as a novel GvHD suppressor without compromising GvL.