Leukemic progenitor cells enable immunosuppression and post-chemotherapy relapse via IL-36-inflammatory monocyte axis

TY - JOUR

T1 - Leukemic progenitor cells enable immunosuppression and post-chemotherapy relapse via IL-36-inflammatory monocyte axis

AU - Guo, He Zhou

AU - Guo, Zi Hua

AU - Yu, Shan He

AU - Niu, Li Ting

AU - Qiang, Wan Ting

AU - Huang, Meng Meng

AU - Tian, Yuan Yuan

AU - Chen, Juan

AU - Yang, Hui

AU - Weng, Xiang Qin

AU - Zhang, Yi

AU - Zhang, Wu

AU - Hu, Shao Yan

AU - Shi, Jun

AU - Zhu, Jiang

N1 - Publisher Copyright: © 2021 The Authors.

PY - 2021/10

Y1 - 2021/10

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85116788970

U2 - 10.1126/sciadv.abg4167

DO - 10.1126/sciadv.abg4167

M3 - Article

C2 - 34623912

SN - 2375-2548

VL - 7

JO - Science advances

JF - Science advances

IS - 41

M1 - abg4167

ER -