LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation
Jamie A. Moore, … , Kristian M. Bowles, Stuart A. Rushworth
Jamie A. Moore, … , Kristian M. Bowles, Stuart A. Rushworth
Published January 6, 2022
Citation Information: J Clin Invest. 2022;132(5):e153157. https://doi.org/10.1172/JCI153157.
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Research Article Hematology Oncology Article has an altmetric score of 156

LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation

Abstract

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.

Authors

Jamie A. Moore, Jayna J. Mistry, Charlotte Hellmich, Rebecca H. Horton, Edyta E. Wojtowicz, Aisha Jibril, Matthew Jefferson, Thomas Wileman, Naiara Beraza, Kristian M. Bowles, Stuart A. Rushworth

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Figure 2

AML disease progression is accelerated in LAP-deficient animals.

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AML disease progression is accelerated in LAP-deficient animals. (A) MN1...
(A) MN1 cells (1 × 106) were injected into busulfan-treated Atg16L1E230+ and Atg16L1E230– mice. (B) BM was extracted and cells were analyzed by flow cytometry for engraftment on days 14 and 20 (n = 5 mice). (C) Kaplan-Meier curve showing the survival of Atg16L1E230+ and Atg16L1E230– mice after injection (n = 5 mice). (D) MEIS/HOXA9 cells (1 × 106) were injected into busulfan-treated Atg16L1E230+ and Atg16L1E230– mice. (E) BM was extracted and cells were analyzed by flow cytometry for engraftment on day 20 (n = 5 mice). (F) Kaplan-Meier curve showing the survival of Atg16L1E230+ and Atg16L1E230– mice after injection (n = 5 mice). (G and H) MN1 cells (1 × 106) were injected into busulfan-treated Atg16L1E230fl/fl Cre+ and Atg16L1E230fl/fl Cre– mice. BM was extracted and cells were analyzed by flow cytometry for engraftment on day 14 (n = 4 mice). (I) CD14+ cells were isolated from blood samples from patients with AML and controls. Cells were then fixed, permeabilized, and stained for LC3 and analyzed by microscopy (n = 5 healthy controls; n = 8 patients with AML). Scale bars: 10 µm. (J) MN1 cells (1 × 106) or vehicle-treated (PBS) cells were injected into busulfan-treated Atg16L1E230+ and Atg16L1E230– mice, and BM was harvested 14 days later. The percentage of AAMs (CD45+Lys6G–CD11b+) in the BM as well as the percentage of CD86+ and CD206+ AAMs were analyzed by flow cytometry (n = 3 mice). (K) The percentage of BMMs (CD45+GR1–CD115lo/intF4/80+) in the BM as well as the percentage of CD86+ and CD206+ BMM cells were analyzed via flow cytometry (n = 3 mice). Data indicate the mean ± SD. *P < 0.05 and **P < 0.01, by Mann-Whitney U test.