Exploring the landscape and function of macrophages in Acute Myeloid Leukemia
With immune therapies being on the rise, an in-depth understanding of the immunological changes in leukemic bone marrow (BM) niches becomes critically relevant. We were triggered by the observation that expression of CD163 in the mononuclear cell population within the bone marrow of acute myeloid leukemia (AML) patients is among one of the best predictors of poor prognosis. Intriguingly however, we identified that this expression does not emerge from the leukemic blasts themselves, but from a myeloid cell population that we could characterize as tumor supportive M2-macrophages.
Next, we studied the impact of tumor associated macrophages (TAMs) in a large cohort of AML patients.
We observed a significant decrease in CD80+-M1-macrophages and increase in CD163/CD206+-M2-macrophages in the BM and peripheral blood of AML patients. A high number of M2-macrophages was found in mutant FLT3-ITD patients and associated with lower overall survival (OS). Furthermore, macrophage and AML primary/cell line co-culture experiments indicated that the presence of M1-macrophages reduced AML growth via apoptosis and cell cycle arrest, while M2-macrophages promoted AML survival, proliferation, and drug resistance. Moreover, the exposure of M1-macrophages to AML cells repolarized M1 into M2-macrophages. Finally, we evaluated the impact of M2-macrophages on leukemogenesis in a xenograft model. It is known that primary APL patient cells are notoriously difficult to engraft in xenograft mice, and we hypothesized that co-injection of M2-macrophages might facilitate engraftment and leukemogenesis. Upon intra-femoral co-transplantation of M2-macrophages, NSGS mice developed full-blown APL with significantly decreased OS, while no engraftment was observed in control mice transplanted with APL blasts alone. Maintenance of self-renewal was shown in a secondary transplant.
We observed that the frequency of M2-macrophages is often upregulated in AML patients, correlating with poor prognosis. Our data further highlight that AMLs cells can modulate the tumour microenvironment into a tumour permissive one, which enhances proliferation and survival, allowing in vivo leukemogenesis of primary patient samples, which are difficult to engraft.