Long-acting pegylated interferon gamma sensitizes AML cells to killing by donor T cells
Vaishali Basu1, Gregory Mannino2, Laura F Mpofu1
1Division of Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO.
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.
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.
