LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation.
LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation.
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DOI：
10.1172/jci153157
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发表时间：
2022-03-01
期刊：
影响因子：
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通讯作者：
Rushworth SA
中科院分区：
文献类型：
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作者：
Moore JA;Mistry JJ;Hellmich C;Horton RH;Wojtowicz EE;Jibril A;Jefferson M;Wileman T;Beraza N;Bowles KM;Rushworth SA
骨髓 (BM) 微环境调节急性髓系白血病 (AML) 的起始、增殖和化疗耐药性。癌细胞死亡后，越来越多的证据表明，剩余的细胞凋亡碎片在调节实体瘤的免疫反应和生长中发挥着重要作用。在这里，我们研究了巨噬细胞 LC3 相关的吞噬作用 (LAP) 在 AML 的骨髓微环境中的作用。 BM 巨噬细胞 (BMM) 的耗竭会增加体内 AML 的生长。我们表明，LAP 是 BMM 吞噬 AML 微环境中死亡和垂死细胞的主要方法。靶向抑制LAP会导致凋亡细胞（AC）和凋亡小体（AB）的积累，从而加速白血病的生长。从机制上讲，BMM 对 AML 衍生 AB 进行 LAP 导致 IFN 基因刺激物 (STING) 通路激活。我们发现 AML 衍生的线粒体损伤相关分子模式由 BMM 通过 LAP 进行处理。此外，AML 衍生的 AB 中线粒体 DNA (mtDNA) 的消耗表明，正是这种 mtDNA 负责在 BMM 中诱导 STING 信号传导。在表型上，我们发现 STING 激活通过与吞噬作用增加相关的机制抑制 AML 生长。总之，我们报告了 AML BM 微环境中凋亡碎片的巨噬细胞 LAP 抑制了肿瘤生长。
The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation, and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for remaining apoptotic debris in regulating the immunologic response to and growth of solid tumors. Here, we investigated the role of macrophage LC3–associated phagocytosis (LAP) within the BM microenvironment of AML. Depletion of BM macrophages (BMMs) increased AML growth in vivo. We show that LAP is the predominate method of BMM phagocytosis of dead and dying cells in the AML microenvironment. Targeted inhibition of LAP led to the accumulation of apoptotic cells (ACs) and apoptotic bodies (ABs), resulting in accelerated leukemia growth. Mechanistically, LAP of AML-derived ABs by BMMs resulted in stimulator of IFN genes (STING) pathway activation. We found that AML-derived mitochondrial damage–associated molecular patterns were processed by BMMs via LAP. Moreover, depletion of mitochondrial DNA (mtDNA) in AML-derived ABs showed that it was this mtDNA that was responsible for the induction of STING signaling in BMMs. Phenotypically, we found that STING activation suppressed AML growth through a mechanism related to increased phagocytosis. In summary, we report that macrophage LAP of apoptotic debris in the AML BM microenvironment suppressed tumor growth.