Macrophages in tumor microenvironments and the progression of tumors

Abstract

Macrophages are widely distributed innate immune cells that play indispensable roles in the innate and adaptive immune response to pathogens and in-tissue homeostasis. Macrophages can be activated by a variety of stimuli and polarized to functionally different phenotypes. Two distinct subsets of macrophages have been proposed, including classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages express a series of proinflammatory cytokines, chemokines, and effector molecules, such as IL-12, IL-23, TNF-α, iNOS and MHCI/II. In contrast, M2 macrophages express a wide array of anti-inflammatory molecules, such as IL-10, TGF-β, and arginase1. In most tumors, the infiltrated macrophages are considered to be of the M2 phenotype, which provides an immunosuppressive microenvironment for tumor growth. Furthermore, tumor-associated macrophages secrete many cytokines, chemokines, and proteases, which promote tumor angiogenesis, growth, metastasis, and immunosuppression. Recently, it was also found that tumor-associated macrophages interact with cancer stem cells. This interaction leads to tumorigenesis, metastasis, and drug resistance. So mediating macrophage to resist tumors is considered to be potential therapy.

Figure 1

Classically and alternatively activated macrophages. Classically polarized macrophages are activated by LPS, IFN-γ, or TNF-α. Alternatively polarized macrophages can be further divided into M2a, M2b, and M2c macrophages. IL-4 and IL-13 always activate macrophages to be M2a macrophages. The main difference between M1 and M2a macrophages is in their metabolism of L-arginine. In M1 macrophages, L-arginine is metabolized into L-citrulline and NO by NOS2, while in M2a macrophages, it is metabolized into polyamine and urea by arginase 1. M2b macrophages are activated by immune complexes, TLRs, or IL-1ra. Finally, M2c macrophages are polarized by IL-10. All of the phenotypes express a series of different cytokines, chemokines, and receptors.

Figure 2

TAM functions in tumor progression. Tumor cells and stromal cells, which produce a series of chemokines and growth factors, induce monocytes to differentiate into macrophages. In the tumor, most macrophages are M2-like, and they express some cytokines, chemokines, and proteases, which promote tumor angiogenesis, metastasis, and immunosuppression.