demonstrated this association in pancreatic cancer cases, as cancer cells co-cultured with irradiated fibroblasts demonstrated greater radioresistance and integrin concentration than did their non-irradiated counterparts (86)

demonstrated this association in pancreatic cancer cases, as cancer cells co-cultured with irradiated fibroblasts demonstrated greater radioresistance and integrin concentration than did their non-irradiated counterparts (86). future treatment modalities. (8). To induce rapid chemotaxis toward inflammatory chemokines, activated T cells have increased expression of surface chemokine receptors, including CXCR3, which, along with its interferon (IFN)–inducible ligands, has been associated with a Th1 WHI-P258 immune WHI-P258 response and accumulation of both T and natural killer cells in the tumor bed (9C11). However, tumors commonly dysregulate normal chemokine pathways and express different chemokines, such as nitrosylated CCL2 and CCL28, which result in the recruitment and accumulation of Tregs, TAMs, immature dendritic cells (DCs), and MDSCs and form an immune-suppressive TME (12). TME conditions are partly responsible for such changes in chemokine networks. Nitrosylation of CCL2, which normally supports tumor-infiltrating lymphocyte trafficking into the tumor core, occurs through the production of reactive nitrogen species in the TME (13). CCL28 is produced as a result of tumor hypoxia and the release of damage-associated pattern molecules (14). In addition, tumors often specifically target chemokines that are responsible for cytotoxic T lymphocyte (CTL) infiltration. One such chemokine is CXCL11, which specifically attracts CXCR3+ CD8+ cells and undergoes proteolytic alterations induced by the tumor, resulting in failure to attract TILs (15). In addition, preclinical and clinical evidence has demonstrated that expression of CCL27, which also plays a role in T-cell homing under inflammatory conditions, is downregulated by hyper-activation of the epidermal growth factor receptor (EGFR)/Ras/mitogen-activated protein kinase (MAPK) signaling pathway in melanoma (16). Overall, WHI-P258 manipulation of chemokine networks in the TME results in an abundance of M2 TAMs and other regulatory components that blunt the antitumor activity of CTLs. In the stroma, both tumor cells and Rabbit Polyclonal to MZF-1 these abundant M2 TAMs secrete various molecules, such as vascular endothelial growth factor (VEGF), interleukin (IL)-10, transforming growth factor (TGF)-, adenosine, and prostaglandin E2, that inhibit DC activation and maturation and suppress the activity of CTLs and natural killer-mediated immunity (17). For example, the production of VEGF, which is a well-known mediator of angiogenesis, can play a strong role in preventing DC precursors from maturing into DCs (18). Likewise, prostaglandin E2 secretion modulates chemokine production in favor of Tregs and MDSCs differentiation while inhibiting CTLs and natural killer cell populations and decreases production of IL-2 and IL-12 (19). M2 TAMs have immune-suppressive roles that extend beyond the production of soluble factors. The immune-excluded phenotype can physically occur via long-lasting interactions between CTLs and TAMs. Peranzoni and colleagues showed that stromal macrophages impede CD8+ T cells from reaching tumor islets by making long-lasting contacts that reduce T-cell motility (20). Upon pharmacological depletion of TAMs, T-cell infiltration and migration into the tumor islets were no longer impeded, and this enhanced the efficacy of anti-programmed cell death protein 1 (PD-1) immunotherapy (20). Clinically, the same study found that lung squamous cell carcinoma patients with high tumor: stroma ratios, which reflected increased CD8+ T-cell infiltration into tumor islets, had better overall survival than did patients with low ratios (20). Tumor vasculature may play a strong role in the stromal mechanisms of immune exclusion. The migration of T cells WHI-P258 through the endothelium, which is often dysregulated as a result of vasculature remodeling, is another challenge to antitumor immunity. For T cells to migrate to the tumor bed, they must adhere to the endothelium (21). However, expression of various endothelial adhesion molecules, such as intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion protein (VCAM)-1, is downregulated in endothelial cells surrounding solid tumors (22). Recently, Motz and colleagues have described a mechanism by which the tumor endothelial barrier regulates T cell migration into tumors (23). In both human and mouse tumor vasculature, the expression of Fas ligand (FasL), which induces apoptosis, was detected, but it was not detected in normal vasculature (23). Additionally, the expression of FasL on endothelium was associated with decreased CD8+ infiltration and accumulation of Tregs, which were resistant to FasL due to higher c-FLIP expression. However, this blunting of CD8+.