2.1.1. Tumor-associated macrophages (TAMs) and immunosuppression

TAMs are the major components of infiltrating immune cells in the tumor site of virtually all types of malignancies. The abundant nature of TAMs within the tumor microenvironment enables them to maintain severe immunosuppression and has been often associated with worst prognosis. During the process of tumor progression, the secretion of tumor-derived soluble factors that support the development of TAM in the local tumor sites includes M-CSF, IL-10, IL-4, and IL-13. Several studies have reported that TAM-derived secreted mediators such as TGF-β, IL-10, arginase 1, prostaglandins, and indoleamine dioxygenase (IDO) make a significant contribution to immunosuppression [13]. Poor antigen presenting capacity of TAMs reduces the tumor-specific T-cell proliferation and response by releasing the immunosuppressive factors, IL-10 and TGF-β [10]. Several studies have reported that the maturation of dendritic cells (DCs) in situ is halted by IL-10 derived from TAM but increases the differentiation of macrophages toward TAM with defective antigen presenting machinery [9, 14]. In contrast, proinflammatory cytokine IL-12 is crucial for the development of CD4+ Th1 response as CD4+ Th1 cells are a major source of IFN-γ. However, autocrine production of IL-10 by TAM is, in part, responsible for the defective LPS/IFN-γ response and reduced expression of IL-12; thereby impaired the cell-mediated immunity in tumor site [15]. Furthermore, TAMs also severely downregulate the expression of other proinflammatory cytokines such as TNF-α, IL-6, CCL3, and IL-1β, upon activation with lipopolysaccharides (LPS) [12]. Immunosuppressive cytokine TGF-β derived from TAMs promotes the development of Th2 cells, and induction and infiltration of CD4+ CD25+ FoxP3+ T cells (Treg) at the tumor site [13] are also regulated by TAMs through secretion of TGF-β and IL-10. Alteration of nutrient starvation of tumor microenvironment is another strategy of tumor-associated myeloid population. Depletion of L-arginine in the tumor microenvironment is also an important mechanism of TAM-mediated T-cell suppression [12]. Metabolization of L-arginine that depends on the activity of two crucial enzymes, nitric-oxide synthase (NOS) and arginase I (ARGI), has been shown to be differentially regulated by macrophages. The expression of iNOS is upregulated by Th1 cytokines, whereas induction of arginase depends on the Th2 cytokines. Thus, in late stage of tumor, high expression of arginase is found to be associated with TAMs. Metabolism of L-arginine by ARGI to urea and L-ornithine is necessary for tumor as L-ornithine is the precursor molecules of many tumor growth factors. Furthermore, depletion of L-arginine from extracellular space inhibits the re-expression of the CD3 ζ chain, which is required for a proper T-cell activity. TAMs display a defective and delayed NFkB activation signaling, which probably provides a molecular mechanism for altered TAM functions, including defective iNOS expression [12].
