Long-acting pegylated interferon gamma sensitizes AML cells to killing by donor T cells

Abstract: Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with the loss of major histocompatibility complex 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 transplantation. 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 tumor necrosis factor alpha (TNF-α), in MHC-II–low AML cells compared with MHC-II–high AML cells from the same samples. Treatment with exogenous interferon gamma (IFN-γ) but not IFN-α or TNF-α restored MHC-II expression in MHC-II–low post-HSCT relapse cells, and IFN-γ treatment of THP1 cells increased alloreactivity of HLA-mismatched donor T cells in vitro. Because recombinant IFN-γ has a short half-life in vivo, we tested whether a novel, long-acting pegylated IFN-γ (peg–IFN-γ) could increase the sensitivity of AML cells to donor T-cell clearance in mouse models. Peg–IFN-γ treatment was well tolerated in healthy mice and led to more robust upregulation of MHC-II expression compared with recombinant IFN-γ. In addition, pretreatment with peg–IFN-γ enhanced AML cell clearance by donor T cells in xenografts, raising the possibility that sensitization of AML cells by exogenous long-acting IFN-γ may be of therapeutic benefit in patients with AML relapsing after HSCT.