LAUSR

Patients with acute myeloid leukemia (AML) often achieve remission after allogeneic hematopoietic cell transplantation (allo-HCT), but subsequently die of relapse that is driven by leukemia cells resistant to elimination by allogeneic T-cells based on decreased MHC-II expression and apoptosis-resistance. Here we demonstrate that mouse-double-minute-2 (MDM2)-inhibition can counteract immune evasion of AML. MDM2-inhibition induced MHC class I and II expression in murine and human AML cells. Using xenografts of human AML and syngeneic mouse models of leukemia, we show that MDM2-inhibition enhanced cytotoxicity against leukemia cells and improved survival. MDM2-inhibition also led to increases in TRAIL-R1/2 on leukemia cells and higher frequencies of CD8+CD27lowPD-1lowTIM-3low T-cells, with features of cytotoxicity (Perforin+CD107a+TRAIL+) and longevity (bcl-2+IL-7R+). CD8+ T-cells isolated from leukemia-bearing MDM2-inhibitor treated allo-HCT recipients exhibited higher glycolytic activity and enrichment for nucleotides and their precursors compared to vehicle-controls. T-cells isolated from MDM2-inhibitor treated AML bearing mice eradicated leukemia in secondary AML-bearing recipients. Mechanistically, the MDM2-inhibitor mediated effects were p53-dependent because p53-knockdown abolished TRAIL-R1/2 and MHC-II-upregulation, while p53-binding to TRAILR1/2-promotors increased upon MDM2-inhibition. The observations in the mouse models were complemented by data from human individuals. Patient-derived AML-cells exhibited increased TRAIL-R1/2 and MHC-II expression upon MDM2-inhibition. In summary, we identified a targetable vulnerability of AML cells to allogeneic T-cell-mediated cytotoxicity, through restoration of p53-dependent TRAIL-R1/2 and MHC-II-production via MDM2-inhibition.