Science Advances Shanghai Jiaotong University Zhujiang/Shi Jun discovered a potential therapeutic target for acute myeloid leukemia

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iNature In most cases of acute myeloid leukemia (AML), chemotherapy can effectively reduce the burden of leukemia and restore immune cell production
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However, endogenous immune surveillance usually fails to recover after chemotherapy, leading to recurrence
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The underlying mechanism of this treatment failure is still poorly understood
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On October 8, 2021, Zhujiang and Shi Jun of Shanghai Jiaotong University published a research paper entitled "Leukemic progenitor cells enable immunosuppression and post-chemotherapy relapse via IL-36–inflammatory monocyte axis" in Science Advances.
The research It shows that abnormal IL-36 production activated by NF-κB is a basic feature of mouse and human leukemia progenitor cells (LP)
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In terms of mechanism, IL-36 directly activates inflammatory monocytes (IM) in the bone marrow, and then prevents the elimination of leukemia mediated by CD8+ T cells and promotes the growth of LP
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While retaining IM, common chemotherapy drugs stimulate residual LP to produce IL-36 through caspase-1 activation, so that this immunosuppressive IL-36-IM axis persists after chemotherapy
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In addition, IM depletion of trabectedin, combined with chemotherapy and PD-1 blockade, can synergistically limit the progression and recurrence of AML
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Collectively, these results indicate that inhibition of the IL-36-IM axis is a potential strategy to improve the treatment of AML
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Acute myeloid leukemia (AML) is a group of common hematopoietic malignancies, characterized by abnormal immature myeloid blasts infiltrating bone marrow (BM) and other hematopoietic tissues, resulting in severe suppression of normal hematopoiesis
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Although most AML patients initially respond to conventional therapies including chemotherapy and allo-BMT (allo-BMT), many of them will relapse within a few months and gain treatment resistance
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Longitudinal studies have shown that AML that relapses after allo-BMT needs to escape graft anti-leukemia immune rejection, while AML that relapses after chemotherapy does not experience the selective pressure generated by endogenous immune surveillance that may recover
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Most AML cases show overwhelming de novo resistance to immune checkpoint blockade, and only a portion of immune-infiltrating AML cases respond to Flotetuzumab
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On the other hand, chronic immunosuppression after organ transplantation greatly increases the incidence of AML
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Therefore, activating endogenous immune surveillance for AML has great potential to improve the treatment of AML by synergizing with other contemporary treatment modalities
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According to reports, both leukemia stem/progenitor cells and their monocyte progeny can suppress and evade immune surveillance
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Since chemotherapy largely avoids the production of leukemia stem/progenitor cells and effectively reduces a large number of leukemia cells, the remaining leukemia stem/progenitor cells may be able to create an immunosuppressive microenvironment that allows possible relapse
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Similarly, in the early stages of leukemia transmission, some leukemia progenitor cells (LP) must resist possible local immune surveillance (for example, in BM)
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However, the underlying mechanisms in these specific situations are still unclear
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Interleukin-36α (IL-36α), three functional paralogs of IL-36β and IL-36γ and the antagonist IL-36Ra constitute the IL-36 family, sharing one IL-36R and IL-1RAcP As a common receptor complex, the abnormal activation of IL-36 signaling is involved in the pathogenesis of many types of autoimmune diseases
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Although IL-36γ, which is artificially expressed in solid tumors, has been shown to promote type I anti-tumor immunity, its role in immune surveillance and regulation against AML has not been reported
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In this study, it was shown that pro-inflammatory LP marked by activation of the nuclear factor-κB (NF-κB) pathway secretes IL-36, and this feature is stimulated by chemotherapy-stimulated caspase-1-IL-1β- NF-κB autocrine signaling pathway persists
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In terms of mechanism, IL-36 activates inflammatory monocytes (IM) in BM, which not only promotes the survival and proliferation of AML cells, but also excludes CD8+ T cell-mediated AML clearance
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Overall, this study shows that inhibiting the IL-36-IM axis is a potential strategy to improve the treatment of AML
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