Abstract
Chemotherapy can effectively reduce the leukemic burden and restore immune cell production in most acute myeloid leukemia (AML) cases. Nevertheless, endogenous immunosurveillance usually fails to recover after chemotherapy, permitting relapse. The underlying mechanisms of this therapeutic failure have remained poorly understood. Here, we show that abnormal IL-36 production activated by NF-κB is an essential feature of mouse and human leukemic progenitor cells (LPs). Mechanistically, IL-36 directly activates inflammatory monocytes (IMs) in bone marrow, which then precludes clearance of leukemia mediated by CD8+ T cells and facilitates LP growth. While sparing IMs, common chemotherapeutic agents stimulate IL-36 production from residual LPs via caspase-1 activation, thereby enabling the persistence of this immunosuppressive IL-36–IM axis after chemotherapy. Furthermore, IM depletion by trabectedin, with chemotherapy and PD-1 blockade, can synergistically restrict AML progression and relapse. Collectively, these results suggest inhibition of the IL-36–IM axis as a potential strategy for improving AML treatment.