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 increased AML growth in-vivo. We showed that LAP is the predominate method of BM macrophage phagocytosis of dead and dying cells in the AML microenvironment. Targeted inhibition of LAP led to accumulation of apoptotic cells (AC) and apoptotic bodies (AB) resulting in accelerated leukemia growth. Mechanistically, LAP of AML derived-AB by BM macrophages, resulted in STING pathway activation. We identified that AML derived mitochondrial damage associated molecular patterns were processed by BM macrophages via LAP. Moreover, depletion of mitochondrial DNA (mtDNA) in AML derived-AB showed that it is this mtDNA which was responsible for the induction of STING signalling in BM macrophages. 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.

Taking the STING out of acute myeloid leukemia through macrophage-mediated phagocytosis

“…One potential clue was the observation that LAP deficiency resulted in the recruitment and activation of cytotoxic T cells in solid tumor models, which could restrain tumor expansion ( 11 ). In the study by Moore and colleagues, LAP deficiency increased CD4 + Th cells in one AML model (MN1), although, unlike prior solid tumor studies, there was no recruitment of cytotoxic CD8 + cells ( 10 ). The authors also found that AML cells promoted the expansion of both tumor-associated macrophages and resident BM macrophages, and neither of these processes was altered when LAP was impaired ( 10 ).…”

“…Further, infusion of ex vivo–expanded NK cells together with the allograft improves outcomes ( 9 ). As demonstrated by Moore et al ( 10 ), another exciting therapeutic strategy centers on modulating macrophage activity within the leukemia TME. In solid tumors, tumor-associated macrophages (TAMs) are composed of different cell populations that can either repress or foster tumor growth ( 11 , 12 ).…”

“…The discovery of CD47 and subsequent clinical trials established the importance of macrophages, not only in tumor progression, but also in responses to antibody-based therapies ( 13 ). However, substantial gaps in our understanding of mechanisms controlling macrophage activity in AML remain, and the work by Moore et al illuminates a surprising mechanism with potential for therapeutic opportunities ( 10 ).…”

“…Together, these findings suggested that LAP mediates immune suppression and tolerance, while defective LAP function could lead to autoimmune disease or defective tumor clearance ( 15 , 16 ). In this issue of the JCI , Moore and authors investigated the role of LAP within the BM microenvironment in AML and uncovered another LAP function ( 10 ).…”

“…Moore et al confirmed that clodronate depleted macrophages within the BM microenvironment and increased the leukemia burden in two additional models of murine AML (MEIS1/HOXA9 and MN1 AML; ref. 10 ). The authors went on to show that BM macrophages from mice with AML had increased phagocytic activity compared with macrophages derived from BM of healthy mice.…”