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 pathway2 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.
Gonçalves Silva I, Yasinska IM, Sakhnevych SS, et al. EBioMedicine 2017; 22: 44–57.
Yasinska IM, et al. Front Immunol 2019;10:1594.
Disclosure Information V.V. Sumbayev: None. I.M. Yasinska: None. S.S. Sakhnevych: None. E. Fasler-Kan: None. B.F. Gibbs: None.
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