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外文期刊>Journal for ImmunoTherapy of Cancer
>P01.17?Tim-3/Galectin-9 pathway controls the ability of malignant cells to escape host immune surveillance. Regulatory mechanisms and therapeutic targets
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P01.17?Tim-3/Galectin-9 pathway controls the ability of malignant cells to escape host immune surveillance. Regulatory mechanisms and therapeutic targets
Background Human cancer cells implement a variety of biochemical mechanisms which allow them to escape host immune surveillance resulting in disease progression. We have reported that the immune receptor Tim-3 and its natural ligand and possible trafficker galectin-9 determine the capability of human acute myeloid leukemia (AML) cells to evade cytotoxic immune attack. 1 Our further studies demonstrated that breast, colorectal and other human solid malignant tumour cells display high activity of this pathway 2 which can also be used for immune evasion. It is, however, important to understand the mechanisms which regulate the biochemical activity of Tim-3/galectin-9 pathway and expression of its components as well as the molecular basis of its capability to impair anti-cancer activity of cytotoxic lymphoid cells. Materials and Methods In this study we used human cancer and non-malignant cell lines as well as primary human malignant tumour samples. We also used primary human T cells and natural killer (NK) cells. Western blot analysis, ELISA, quantitative real-time PCR, on-cell Western, immunohistochemistry, flow cytometry and biochemical assays were used as key instrumentals to conduct measurements. Results We found that galectin-9 is used by human cancer cells to escape host immune surveillance. Cancer cells use various biochemical pathways to overexpress galectin-9. Regardless the biochemical background, transforming growth factor-beta (TGF-β) and transcription factor Smad-3 play crucial role in galectin-9 expression in human cancer cells. We identified the key receptors through which galectin-9 can then trigger killing of cytotoxic T lymphocytes and impairing of anti-cancer activity of natural killer cells. Conclusions In this work, we report the biochemical mechanisms underlying overexpression of galectin-9 in human malignant tumour cells and its differential effects on human cytotoxic lymphoid cells.
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