Long-acting pegylated Interferon Gamma (pegIFNG) sensitizes AML cells to killing by donor T cells.

AML relapse after allogeneic hematopoietic stem cell transplantation (HCT) is associated with loss of MHC class II (MHC-II) expression on AML cells. Although the mechanisms by which this occurs are unknown, the loss of antigen presentation by MHC-II may contribute to AML relapse after transplant. In this study, we performed single cell RNA sequencing on patient samples with MHC-II loss and observed downregulation of inflammatory signaling pathways, including type I and II interferons and TNFα, in MHC-II-low AML cells compared to MHC-II-high AML cells from the same samples. Treatment with exogenous interferon gamma (IFNG) but not IFNA or TNFA restored MHC-II expression in MHC-II-low post-HCT relapse cells, and IFNG treatment of THP1 cells increased alloreactivity of HLA-mismatched donor T cells in vitro. Since recombinant IFNG has a short half-life in vivo, we tested whether a novel, long-acting pegylated IFNG (peg-IFNG) could increase sensitivity of AML cells to donor T cell clearance in mouse models. Peg-IFNG treatment was well-tolerated in healthy mice and led to more robust upregulation of MHC-II expression compared to recombinant IFNG. Additionally, pretreatment with peg-IFNG treatment enhanced AML cell clearance by donor T cells in xenografts, raising the possibility that sensitization of AML cells by exogenous long-acting IFNG may be of therapeutic benefit in AML patients relapsing after HCT.