In addition, similar

to FasL and RCAS1, CD70 overexpressed on RCC promotes lymphocyte Selleckchem AG-120 apoptosis by binding to its receptor CD27, indicating a proapoptotic role of CD70 in the elimination of TICs as well [82]. All these observations suggest that the direct induction of TIC apoptosis by persistent expression of FasL, RCAS1 this website or perhaps other apoptosis-inducing ligands (e.g. CD70) on carcinoma cells plays a role in the ability of carcinoma cells to escape from the anti-carcinoma immunity. Suppression of TIC activity by molecular and cellular factors Immunoregulatory cytokine/cytokine-like: Transforming growth factor (TGF)-β1 and Galectin-1 (Gal-1) TGF-β1 is a multifunctional cytokine involved in immunosuppression. Numerous clinical studies have demonstrated that a higher level of TGF-β1 expression is significantly

associated with an invasive phenotype of tumors or metastases in patients [83–86]. In vitro a significant amount of TGF-β1 is produced in the poorly differentiated prostate carcinoma cell lines but not in well-differentiated cells [87]. These data imply that TGF-β1 may increase metastasis by a paracrine matter, such as suppression of local immune response or increased angiogenesis. Indeed, in the biopsies of cervical carcinoma tumors, an inverse relationship between TGF-β1 expression in tumor cells and the extent of TICs is demonstrated [88]. Raf inhibitor This clinical observation is further confirmed by several experimental studies. In a mouse skin explant model, TGF-β1 is produced by progressor types but not regressor squamous cell carcinoma acetylcholine lines, and this tumor-derived cytokine inhibits migration of professional APCs, Langerhans cells (LCs), and keeps them in an immature

form [89], or transgenic expression of TGF-β1 enhances growth of regressor squamous carcinoma cells in vitro and in vivo just like progressor phenotype, and reduces the number of infiltrating LCs, CD4+ and CD8+ T cells [90]. A further study with invasive colon carcinoma U9A cell line shows that decreasing TGF-β1 expression by antisense reduces the invasive activity and metastasis of tumor cells to the liver [91]. All these studies suggest that carcinoma-derived TGF-β plays an important role in the tumor metastasis, which may be caused by its immune suppressive function. Gal-1 is a member of β-galacosidess binding protein family (galectins), and is a recently identified immunoregulatory cytokine-like molecule in cancer [92]. It has been documented that Gal-1 exhibits immunoregulatory effects by which it controls immune cell trafficking, regulates activation of dendritic cells (DCs) and induces T-cell apoptosis [93].