Repolarizing heterogeneous leukemia-associated macrophages with more M1 characteristics eliminates their pro-leukemic effects

Abstract

Macrophages exhibit phenotypic heterogeneity under both physiological and pathological conditions. Applications targeting M2-like tumor-associated macrophages (TAMs) improve outcome in solid tumors. Considerable differences are detected between leukemia-associated macrophages (LAMs) and TAMs. However, application to induce M1 characteristics in heterogeneous LAMs has not been established. Here we analyzed clinical relevance of macrophage phenotypes in human acute myeloid leukemia (AML), studied phenotypic evolution of bone marrow (BM) and spleen (SP) LAMs in mouse AML and T cell acute lymphoblastic leukemia (T-ALL) models, explored mechanism leading to different LAM phenotypes and tried to eliminate pro-leukemic effects by inducing M1 characteristics. The results showed that more M2-like LAMs but not total LAMs correlated with worse prognosis in AML patients. Heterogeneity of LAM activation in tissue-specific leukemic microenvironments was observed in both AML and ALL models, SP LAMs evolved with more M2 characteristics while BM LAMs with more M1 characteristics. Furthermore, IRF7 contributed to M1 characteristics through the activation of SAPK/JNK pathway. Moreover, targeting IRF7-SAPK/JNK pathway to induce M1 characteristics in LAMs contributed to prolonged survival in leukemia mice. Our study provides the potential target for macrophage based immuno-therapy strategy against leukemia.

Monocyte-Derived Leukemia-Associated Macrophages Facilitate Extramedullary Distribution of T-cell Acute Lymphoblastic Leukemia Cells

“…A two-dimensional illustration was established to describe the activation phenotype of macrophages (15). For each gene, the value of the Ly6C + F4/80 + macrophage subset from normal spleen or liver was designated as 0, respectively.…”

“…The LAM subsets showed considerable differences ( Figure 2F). To obtain an intuitive views of the phenotypic evolution of LAM subsets, a two-dimensional illustration of macrophage phenotypes was used (15). Interestingly, Ly6C + LAM was in M1 area at the early and middle stages of leukemia, whereas both splenic Ly6Cand F4/80 hi LAM was in M2 area during leukemia progression.…”

“…Leukemia-associated macrophages (LAM) are different from TAM in gene expression and activation phenotype (14). It seems that LAM is M2-like macrophages with pro-leukemic effects since repolarizing LAM with more M1-associated characteristics (15) or depletion of patrolling monocytes and macrophages delays leukemia progression (16). However, the recruitment of different immune cells into the leukemic microenvironment is observed (14,(17)(18)(19)(20), and LAM may also participate in the leukemia-induced inflammation and exhibit M1-like characteristics.…”

Tumor-Associated Macrophages in Hematologic Malignancies: New Insights and Targeted Therapies

“…Yang et al further confirmed that the number of CD163 + M2-like TAMs was correlated with worse prognosis in AML patients with splenic TAMs exhibiting more M2-characteristics than BM-TAMs. Additionally, they found that Interferon Regulatory Factor 7 (IRF7) contributed to the M1-polarization of TAMs through activation of the SAPK/JNK pathway and subsequent activation of the IRF7-SAPK/JNK pathway resulted in more M1-like TAMs, which was correlated with prolonged survival in leukemic mice [28].…”

The Interplay Between the Genetic and Immune Landscapes of AML: Mechanisms and Implications for Risk Stratification and Therapy

“…AML promotes the polarization of leukemia-supporting macrophages (47). Yang and colleagues further found that, in patients, leukemia associated macrophages are heterogeneous, with both M1- and M2-like leukemia associated macrophages (48). M2-like leukemia associated macrophages were associated with a poor prognosis.…”