2.1.2. TAMs as promising therapeutic targets in cancer therapy

humoral immunity and wound healing [11]. Interestingly in the context of tumor immune response, reports highlights that macrophages in tumor microenvironment are biased away from the M1 to M2 type macrophages and known as tumor-associated macrophages (TAMs) [12]. During late-stage tumor progression, TAMs exhibit an IL-12low IL-10high phenotype with low tumoricidal activity [12] in TME. Growing body of literature has well established the fact that TAMs have been known to provide a favorable microenvironment for tumor growth,

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

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

CD25+

FoxP3+ T cells (Treg)

2.1.1. Tumor-associated macrophages (TAMs) and immunosuppression

the development of Th2 cells, and induction and infiltration of CD4+

tumor survival, and angiogenesis [11].

172 Anti-cancer Drugs - Nature, Synthesis and Cell

expression [12].

Accumulated evidence has demonstrated that immunosuppressive nature of TAM favors tumor cells during tumor development and invasion, suggesting TAM as a target for clinical therapy. TAM-targeting cancer therapy involves on the strategy either by inhibition of TAM recruitment at local tumor site or by modulation of their behavior from protumorigenic M2 to antitumor M1 phenotype. The inhibition of recruitment of TAMs at tumor site can be achieved by targeting chemokine and their receptors as well as selective killing of TAM. Treatment of Met-CCL5 (receptor antagonist of CCL5) significantly reduces the number of macrophage infiltration at tumor site and promotes tumor regression [16]. The pharmacological inhibition of CCL2 with bindarit significantly reduces infiltration of macrophage and suppresses tumor growth [17]. Some studies have also shown that antitumor drug trabectedin exerts cytotoxicity on TAMs without hampering lymphoid subsets [13]. Combination of zoledronic acid with sorafenib dramatically decreases macrophage population, resulting in the enhancement of antitumor effect [16]. A number of other drugs that have also known to inhibit macrophage infiltration include thalidomide, pentoxifylline, and genistein [16]. Furthermore, inhibition of CSF-1R signaling by antibody is also associated with TAM infiltration and tumor regression [18]. Reprogramming of M2 like TAMs toward M1 type macrophage is another potential therapeutic approach. Several studies have shown that activation of TLR signaling stimulates M1 polarized macrophage response [19]. Restoration of IKKβ/NF-kβ pathway is another promising strategy to restore M1 macrophage-mediated intratumoral cytotoxicity [20]. Studies in this direction reveal that combination of CpG plus an anti-IL-10 receptor antibody switched infiltrating macrophages to M1 through restoration of NF-kβ activation thereby promote inflammatory functions [19]. These data suggest that switching the TAM phenotype from M2 to M1 during tumor progression may promote antitumor activities.
