Targeting SLP76/ITK Signaling Interaction Separates GBHD from GVL in Allo-HSCT

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for relapsed hematological malignancies, due to graft-versus-leukemia (GVL) activity mediated by alloreactive donor T cells. However, graft-versus-host disease (GVHD) is also primarily mediated by the same donor T cells. Here we assessed the role of T cells with attenuated TCR-mediated ITK activation in mediating GVL vs GVHD effects after allo-HSCT. T cells from mice with genomic knock-in to express a tyrosine to phenylalanine mutation at position 145 (Y145F) of the adaptor protein SLP-76 display defective TCR-mediated activation of the downstream kinase ITK. Alloreactive T cells from SLP76 Y145F knock-in (KI) mice did not cause GVHD but preserved cytotoxicity, accompanied by upregulation of Eomesodermin (Eomes), which was necessary for GVL function. We developed a novel peptide that can specifically inhibit SLP76 and ITK interactions, resulting in decrease phosphorylation of PLCγ1, ERK and reduce cytokine production in human T cells. This peptide inhibited donor T cell-mediated GVHD while maintaining GVL effects. Altogether, our data suggest that inhibiting SLP-76/ITK interaction could be a therapeutic strategy to reduce GVHD while maintaining the beneficial GVL effects after allo-HSCT treatment.