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

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Chemotherapy effectively reduces leukemia burden but often fails to restore immune surveillance, leading to relapse in acute myeloid leukemia (AML).
• The mechanisms behind this post-chemotherapy immune failure in AML are not well understood.
• Leukemic progenitor cells (LPs) are implicated in disease persistence and relapse.

Purpose of the Study:

• To elucidate the mechanisms underlying immune failure after chemotherapy in AML.
• To identify novel therapeutic targets for preventing AML relapse.

Main Methods:

• Investigated IL-36 production in mouse and human AML models.
• Analyzed the role of NF-κB and caspase-1 in IL-36 activation.
• Examined the interaction between IL-36 and inflammatory monocytes (IMs).
• Assessed the impact of IM depletion and PD-1 blockade on AML progression.

Main Results:

• Abnormal IL-36 production, activated by NF-κB, is a hallmark of AML leukemic progenitor cells (LPs).
• IL-36 activates inflammatory monocytes (IMs), which impair CD8+ T cell-mediated leukemia clearance and promote LP growth.
• Chemotherapy enhances IL-36 production from residual LPs via caspase-1, sustaining an immunosuppressive IL-36–IM axis.
• Combined treatment with chemotherapy, PD-1 blockade, and trabectedin (IM depletion) synergistically inhibited AML progression and relapse.

Conclusions:

• The IL-36–IM axis is a critical mechanism of immune suppression and therapeutic failure in AML.
• Targeting the IL-36–IM axis presents a promising strategy for improving AML treatment and preventing relapse.