Role and Mechanisms of Tumor-Associated Macrophages in Hematological Malignancies

Abstract

Mounting evidence has revealed that many nontumor cells in the tumor microenvironment, such as fibroblasts, endothelial cells, mesenchymal stem cells, and leukocytes, are strongly involved in tumor progression. In hematological malignancies, tumor-associated macrophages (TAMs) are considered to be an important component that promotes tumor growth and can be polarized into different phenotypes with protumor or antitumor roles. This Review emphasizes research related to the role and mechanisms of TAMs in hematological malignancies. TAMs lead to poor prognosis by influencing tumor progression at the molecular level, including nurturing cancer stem cells and laying the foundation for metastasis. Although detailed molecular mechanisms have not been clarified, TAMs may be a new therapeutic target in hematological disease treatment.

Keywords: leukemia; lymphoma; macrophage; myeloma; prognosis.

Figure 1

Tumor-associated macrophages could be alternatively activated related to tumor progression and metastasis. M2 TAMs, with a low antigen-presenting capability, get involved in angiogenesis, tumor cell invasion, resistance to therapy, and release of anti-inflammatory molecules, such as CCL17/18/22, TGF-β, IL-10. M1 TAMs could provoke a Th-1 response and secrete pro-inflammatory molecules, such as TNF-α, NO, CXCL9/10/11, IL-1/6/12/23. TNF, tumor necrosis factor; NO, nitric oxide; CXCL, chemokine ligands with CX3-C motif; IL, interleukin; TGF, tumor growth factor.

Figure 2

Schematic representations of mechanisms between TAMs and tumor cells in Hodgkin lymphoma and non-Hodgkin lymphoma (A), myeloma (B), and leukemia (C). In the different tumor microenvironment, TAMs infiltrate different tumor tissue to promote tumor growth. (A) In Hodgkin lymphoma, TAMs can activate HL cell proliferation through the STAT3 pathway and PI3K-Akt pathway. Besides, M1 macrophage polarization can be predominated by the NF-κB and STAT1 pathways in non-Hodgkin lymphoma. (B) CCL2 induces MCPIP1 expression via the JAK2-STAT3 signaling pathway in the MM bone marrow microenvironment. TAMs can also secrete proangiogenic cytokines like VEGF in MM microenvironment. (C) In the leukemia microenvironment, CSF-1R signaling paves the way for TAM recruitment. Gfi1 polarizes M1 phenotype macrophages into M2 macrophages to suppress the immune system and MOZ is a direct target of miR-223 promoting monocyte-to-macrophage development and M1 polarization. STAT3, signal transducer and activator of transcription; EGF, epidermal growth factor; IDO-1, indoleamine 2,3-dioxygenase; CSF1R, colony-stimulating factor receptor; CSF-1, colony-stimulating factor-1; GM-CSF, granulocyte macrophage-colony stimulating factor; TNF- α, tumor necrosis factor-α; NSE, neuron-specific enolase; VEGF, vascular endothelial growth factor; COX-2, cyclooxygenase-2; MOZ, monocytic leukemia zinc-finger; Gfi1, growth factor independent 1; Arg-2, arginase-1; PB, peripheral blood; TAM, tumor-associated macrophage.