M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism

It is increasingly becoming clear that cancers are a symbiosis of diverse cell types and tumor clones. Combined single-cell RNA sequencing, flow cytometry, and immunohistochemistry studies of the innate immune compartment in the bone marrow of patients with acute myeloid leukemia (AML) reveal a shift toward a tumor-supportive M2-polarized macrophage landscape with an altered transcriptional program, with enhanced fatty acid oxidation and NAD+ generation. Functionally, these AML-associated macrophages display decreased phagocytic activity and intra-bone marrow coinjection of M2 macrophages together with leukemic blasts strongly enhances in vivo transformation potential. A 2-day in vitro exposure to M2 macrophages results in the accumulation of CALRlow leukemic blast cells, which are now protected against phagocytosis. Moreover, M2exposed trained leukemic blasts display increased mitochondrial metabolism, in part mediated via mitochondrial transfer. Our study provides insight into the mechanisms by which the immune landscape contributes to aggressive leukemia development and provides alternatives for targeting strategies aimed at the tumor microenvironment.

Automated summary

Research findings indicate that in acute myeloid leukemia (AML) patients, there is a shift towards a tumor-supportive environment of M2-polarized macrophages with altered transcriptional program. These AML-associated macrophages display decreased phagocytic activity and enhance the in vivo transformation potential when co-injected with leukemic blasts. Additionally, exposure to M2 macrophages leads to the accumulation of CALRlow leukemic blast cells, which are protected against phagocytosis and display increased mitochondrial metabolism.