In summary, CSCs/TICs express soluble and membrane-bound molecules that modulate immune responses and protect cells from immune system attack. The STAT3 pathway plays an essential role in tumor-mediated immunosuppression by inhibiting macrophage activation Difloxacin HCl (51). drug resistance and metastasis, we also comment on the crucial role of key molecules involved in controlling CSCs/TICs properties; such molecules are essential to detect and eliminate CSCs/TICs. Monoclonal antibodies, antibody constructs and vaccines have been designed to take action against CSCs/TICs, with demonstrated efficacy in human cancer xenografts and some antitumor activity in human clinical studies. Therefore, therapeutic strategies that selectively target CSCs/TICs warrant further investigation. Better understanding of the conversation between CSCs and tumor immunology may help to identify strategies to eradicate the minor subpopulation that escapes standard therapy attack, thus providing a solution to the problem of drug resistance and metastasis. (42). In Difloxacin HCl glioblastoma, CSC/TIC survival has been found to be dependent on secretion of associated angiogenic factors such as vascular endothelial growth factor (VEGF), macrophage-chemoattractant protein-1 (MCP-1), macrophage inhibitory factor (MIF), growth related oncogene alfa (GRO) and ecotaxin (43). Also, TGF, IL-6 Difloxacin HCl and IL-8 expression are downregulated in CSCs/TICs (43). In addition, stromal fibroblasts of the tumor microenvironment may be involved in regulating CSC/TIC generation by release of CCL-2 (44). Breast cancer and glioblastoma CSCs/TICs secrete more TGF than normal cancer cells (45). Colon CSCs/TICs secrete IL-4, which promotes drug resistance and inhibits anti-tumor immune responses (46). CD200 is also expressed in CSCs/TICs and plays an important role in immune escape (47). Anti-apoptotic molecules like bcl-2, bcl-xL and survivin protect cells against chemotherapy as well as conferring increased resistance to apoptosis-inducing immune effectors like T or NK cells (48). In a similar manner, the PI3K/Akt pathway mediates chemoresistance and tumor immune escape (49). HER2 interferes with antigen processing and presentation and is key to maintenance of CSCs in luminal breast cancer (50). In summary, CSCs/TICs express soluble and membrane-bound molecules that modulate immune responses and protect cells from immune system attack. The STAT3 pathway plays an essential role in tumor-mediated immunosuppression by inhibiting macrophage activation (51). STAT3 pathway also reduces the cellular cytotoxicity of NK cells and neutrophiles as well as expression of MHC II, CD80, CD86 and IL-12 in dendritic cells (DCs), rendering them unable to activate T cells and initiate antitumor immunity (52). In addition, STAT3 regulates transcription of immunosuppressive factors such as IL-10, VEGF, PGE2 and TGF- (53). It has been shown that STAT3 signaling is up-regulated in glioma CSC/TICs, and growth and self-renewal of this subpopulation LAMP2 is dependent on this pathway. CSCs/TICs also secrete some factors that induce STAT3 phosphorylation in immune cells (54). Tumor-associated antigens (TAAs) expressed by CSCs/TICs CSCs/TICs express TAAs, which characterize their condition of stemness and can be recognized by T cells. TAAs are classed as different subgroups of molecules (41,55) as follows: Differentiation antigens from which the tumor derives and which could also be expressed by normal cells, i.e., carcino-embryonic antigen (CEA) in colon cancer, mucin-1 (MUC-1) in breast cancer, and gp100 and tyrosinase in melanoma (56); hTERT and surviving antigens, and other apoptosis-inhibitory proteins expressed by non-stem cancer cells in addition to subsets of normal cells (57); Cancet-testis (CT) antigens such as Melanoma-associated-antigen-A3 (MAGE-A3) and A4 and NY-ESO1 expressed in normal cells, tumor cells and CSCs/TICs (57); Mutated antigens deriving from somatic point mutations in tumor cells that can result in entirely new epitopes recognizable by the immune system (58). In melanoma, the CSC/TIC subpopulation that express ATP-binding cassette sub-family B member 5 (ABCB5) elicits tumor cell dissemination through mediation of chemotherapy resistance, has low levels of lineage-related and CT antigens (59). However, the CD133+ melanoma cell subpopulation has high expression of NY-ESO1 cancer testis antigen as well as susceptibility to specific T cells (60). The TAA DDX3X has been found in CD133+ CSCs/TICs in melanoma and many cancers, conferring immunogenicity on these cells and their ability to induce T-cell dependent protection against murine cancer growth (61). In contrast, the CD271+ CSC/TIC melanoma subpopulation is deficient in the expression of both lineage-related and CT antigens, making their removal by immune T cells difficult. This has been correlated with progression and metastasis of these cells. As such, melanoma cells Difloxacin HCl offer a good example of multiple CSC/TIC subpopulations with different antigen expression patterns (62). None of these potential TAAs seem to be a specific marker of CSCs/TICs since they may also be expressed in both tumoral and normal cells. However, T cell responses against TAAs are expressed by CSCs/TICs, such as.