Tumor-associated macrophages: an accomplice in solid tumor progression

Abstract

In many solid tumor types, tumor-associated macrophages (TAMs) are important components of the tumor microenvironment (TME). Moreover, TAMs infiltration is strongly associated with poor survival in solid tumor patients. In this review, we describe the origins of TAMs and their polarization state dictated by the TME. We also specifically focus on the role of TAMs in promoting tumor growth, enhancing cancer cells resistance to chemotherapy and radiotherapy, promoting tumor angiogenesis, inducing tumor migration and invasion and metastasis, activating immunosuppression. In addition, we discuss TAMs can be used as therapeutic targets of solid tumor in clinics. The therapeutic strategies include clearing macrophages and inhibiting the activation of TAMs, promoting macrophage phagocytic activity, limiting monocyte recruitment and other targeted TAMs therapies.

Keywords: Angiogenesis; Chemotherapy and radiotherapy resistance; Immunosuppression; Invasion; Metastasis; Migration; Solid tumor; Therapeutic target; Tumor growth; Tumor-associated macrophages.

Fig. 1

The polarization model of macrophage from monocyte differentiation. a. In conventional binary model, macrophages polarize into two subtypes, M1 macrophages with marker such as MHC-II, CD68, CD80, CD86 and M2 subtypes with marker such as CD163, CD200R, MGL-1, MGL-2. In response to different factors stimulation, M2 polarization is represented by four different phenotypes, including M2a (IL-4), M2b (immune complexes (IC) and TLR ligands), M2c (IL-10 and TGF-β) and M2-like (growth factors and cytokines in TME like M-CSF). b. In spectral polarization model, monocytes are differentiated into different subtypes of macrophages with different marker. The surface of TAMs marked with CD163, Fc fragment of IgG, C-type lectin domains and HSP. Other subtypes of macrophages have different marker such as CD169, TLR, MARCO, IFN-γ

Fig. 2

Macrophage differentiation and their characteristics. M1 macrophages are activated by IFN-γ, LPS or TLR ligands, expressing MHC-II, CD68, CD80, CD86, and secreting IL-6, IL-12, IL-23, and exerting pro-inflammatory, cytotoxic and tumoricidal roles. On the contrary, M2 macrophages and TAMs exert immunosuppressive and pro-tumorigenic roles. In general, TAMs are thought to more closely resembleM2 macrophages. Both TAMs and M2 macrophages are activated by helper T cell 2 cytokines IL-4 and IL-13, expressing CD163, CD206, Arg1, and secreting IL-10 and TGFβ. However, TAMs show some characteristics different from M2 macrophages. For example, TAMs express Fc of IgG, C-type lectin, HSP, and secret CCL2 and CCL5.M2 macrophages express high levels of MGL1 and MGL2, members of the macrophage galactose type C-lectin family

Fig. 3

Main roles of tumor-associated macrophages in tumorigenesis. Special markers and different factors derived from TAMs trigger multiple processes of tumor initiation and development. Schematic represents the impact of the tumor-associated macrophages (TAMs) in promoting tumor growth, angiogenesis, Treg cells induction, metabolic starvation of T cells, cancer stem cells induction, T cells inactivation, epithelial-mesenchymal transition (EMT), invasion, migration and metastasis. TAMs promote tumorigenesis by secreting some factors and expressing some proteins. For instance, epidermal growth factor, CSF-1 and MMPs secreted by TAMs promote tumor migration and invasion. TAMs promote angiogenesis and tumor growth by secreting VEGF and PDGF

Fig. 4

Main therapeutic strategies to target tumor-associated macrophages. The therapeutic strategies include following strategies: 1) clearing macrophages and inhibiting the activation of TAMs like targeting CSF-1/CSF-1R signaling to suppress tumor growth, 2) promoting macrophage phagocytic activity by blocking CD47-SIRP-α signaling, 3) limiting monocyte recruitment via targeting CCL2R, 4) others therapies by targeting TAMs such as inhibition of PD-L1 antibody to promote macrophage phagocytic activity