TLRs expressed in normal epithelial cells appear to contribute to carcinogenesis through NF-κB upregulation and subsequent production of antiapoptotic factors such as Bcl-x, c-IAP-1 and c-IAP-2. By selleckchem contrast, TLRs expressed in cancer cells appear to promote tumor progression by facilitating cell survival and migration in a tumor microenvironment characterized by chronic inflammation and PAMPs [31, 32]. Cytokines and Chemokines Activated Through TLR Signals In our study of the immune response to stimulation of specific TLRs in melanoma cell lines [5], we demonstrated that exposure of cells

to ligands specific for TLR2-4 significantly upregulated proinflammatory cytokines (TNFα, G-CSF, IL-1a, and IL-6), proinflammatory chemokines (CCL2 and CXCL2), an immunsuppressive cytokine (IL-10), and an inflammatory factor (COX-2). Ligation of TLRs expressed in cancer cells reportedly also increases TGFβ, IL-8, CXCR4, ICAM-1 and VEGF [6, 12, 13, 33]. Almost all of these cytokines and chemokines promote tumor progression, and their presence characterizes the tumor microenvironment’s active release of various factors that have multiple effects on tumor cells, www.selleckchem.com/products/stattic.html immune cells and normal cells. TGFβ, VEGF, CCL22 and IL-10

can induce CD4+CD25+Foxp3+ regulatory T cells (Tregs) in the tumor microenvironment and tumor-draining regional lymph nodes of cancer patients [16, 34]. These Tregs secrete additional IL-10 and TGFβ, which suppress anti-tumor

functions of non-Treg T cells. Elevated tumor levels of Tregs are linked to poor prognosis in several cancers [35]. IL-10, an immunsuppressive cytokine, upregulates expression of alternatively activated myeloid cells (M2c) in tumor-associated macrophages (TAMs). M2c cells release MLN2238 in vivo angiogenic and lymphoangiogenic factors that promote lymphatic metastasis of cancer cells [36]. Inflammatory mediators IL-1b, IL-6 and PGE2 recruit myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment [37]. MDSCs have recently been recognized as critical mediators of cancer progression; they inhibit the anti-tumor immune response by release of arginase, nitric oxide synthase (NOS) and TGFβ [15, 38]. Additionally, mature myeloid DCs induce a strong T helper 1 (Th1)—type immune response and are considered potent inducers others of TAA-specific immunity. However, in several cancers the dominant population of DCs in the tumor microenvironment is not functionally mature DCs but dysfunctional DCs. Differentiation and maturation of these myeloid DCs are profoundly suppressed by factors present in the tumor microenvironment, including VEGF, IL-6, IL-1, TGFβ, COX-2 and PGE2 [23]. Cancer cells also induce CXCL12, TNFα and IL-8. CXCL12 recruits plasmacytoid DCs that express CXCR4, the receptor of CXCL12, into the tumor microenvironment. These plasmacytoid DCs induce significant IL-10 production by T cells and therefore act as immunsuppressants.