Metastasis followed by the tumor development is the primary cause of

Metastasis followed by the tumor development is the primary cause of death for cancer patients. possible therapeutic targets against these Rabbit Polyclonal to RPC8 MDSCs. producing an immune-suppressive environment in the development and progression of tumor metastasis. Tumor-induced immunosuppression has been recognized as an essential element in tumor progression (1). Research has shown that cancer cells consistently induce local immunosuppression and then create systemic immunosuppression immune-suppressive cells and cytokines (2). However, the underlying molecular mechanisms are not clear. Recent reports showed that immune responses in cancer patients are negatively regulated by immunosuppressive cells, mainly T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which suppress exuberant immune system activation and promote immunologic tolerance (3, 4). Lines of studies further defined that MDSCs can modulate the development and induction of Tregs (5). MDSCs are known to synergize with Tregs to prevent tumor immunity (6). However, the mechanisms of remote tumor cell-induced organ tolerance still require SCH-503034 further clarification. MDSCs, a heterogeneous of immune cells including immature DCs, macrophages, granulocytes, and other myeloid cells in early stages of their differentiation, usually express CD11b, CD33, and low levels of leukocyte antigen-DR in humans or CD11b and Gr1 in mice (7, 8). As reported by Gabrilovich and other scientists, as MDSC accumulated during advanced cancer stages, they exerted an immune-regulatory role and could inhibit many immune cells: CD4+, CD8+, NK, Tregs, etc. (3, 9, 10). Several mechanisms of MDSC suppressive functions have been described, including l-arginine depletion by the enzymes arginase 1 (Arg-1) or inducible nitric oxide synthase (iNOS) and generation of reactive oxygen species (ROS) (11C13). Moreover, MDSCs also secreted many immune-suppressive cytokines, such as IL-6, IL-10, and transforming growth factor (TGF-) (14). However, other mechanisms may have not been identified. The liver is a blood-enriched organ and contains abundant innate and adaptive immune cell subtypes. MDSCs in hepatocellular carcinoma patients regulate the innate system and contribute to immune suppressor networks (15). However, liver tolerance SCH-503034 mechanisms induced by remote tumor inoculated subcutaneously (s.c.) outside the liver are uncertain. A T cell-dependent experimental hepatitis in mice induced by concanavalin A (Con A) was reported in 1990 by Tiegs (16). Con A-induced acute hepatitis is well documented and imitates human autoimmune diseases. IFN- plays a critical role in T cell-dependent liver injury in mice initiated by Con A (17, 18). In our previous studies, IFN- is critical for tumor immunity and T cells provide the early source of IFN- (19). In the model of SCH-503034 Con A-induced hepatitis, NK or NKT cells detrimented the liver damage trough making IFN-, which was negatively regulated by T cells (20). In this study, we intend to investigate the immune tolerance in the liver of tumor-bearing (TB) mice using Con A-induced hepatitis as the readout of liver immune response. The TGF- has three isoforms in mammalian animals, including TGF-1, TGF-2, and TGF-3 that exert diverse roles in controlling cell proliferation, differentiation, wound healing, immune systems, and some pathological processes, e.g., fibrosis and cancer (21, 22). TGF-1 is most highly expressed by immune cells, and a malfunction in this signaling pathway resulted in tumorigenesis (23). Increased TGF- production has been reported in both human cancer patients and animal models, which is usually considered as a negative prognostic indicator (24). Pathological forms of TGF- signaling promote tumor evasion of immune surveillance, tumor growth, and metastasis. Decreased TGF- signaling reduces formation of gastrointestinal tumors (25). Our previous study also showed that tumor-derived TGF- contributed to both tumor growth and tumor immunity (26). TGF- exists in two forms: membrane bounded and soluble (27). However, the role of tumor-derived TGF- in MDSC recruitment regulation was unclear. In this report, we investigated the mechanisms of liver immune suppression induced by remote tumor cells. We demonstrated that growing tumor cells triggered the influx of MDSCs into the liver, and these MDSCs then suppressed the function of NKT cells through their membrane-bound TGF-. Materials and Methods Mice C57BL/6J [wild-type (WT)].