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  • Cysteine cathepsins L and X differentially modulate interactions between myeloid-derived suppressor cells and tumor cells
    Jakoš, Tanja ...
    Increased proteolytic activity of cysteine cathepsins has long been known to facilitate malignant progression, and it has also been associated with tumor-promoting roles of myeloid-derived suppressor ... cells (MDSCs). Consequently, cysteine cathepsins have gained much attention as potential targets for cancer therapies. However, cross-talk between tumor cells and MDSCs needs to be taken into account when studying the efficacy of cathepsin inhibitors as anti-cancer agents. Here, we demonstrate the potential of the MDA-MB-231 breast cancer cell line to generate functional MDSCs from CD14+ cells of healthy human donors. During this transition to MDSCs, the overall levels of cysteine cathepsins increased, with the largest responses for cathepsins L and X. We used small-molecule inhibitors of cathepsins L and X (i.e., CLIK-148, Z9, respectively) to investigate their functional impact on tumor cells and immune cells in this co-culture system. Interactions with peripheral blood mononuclear cells reduced MDA-MB-231 cell invasion, while inhibition of cathepsin X activity by Z9 restored invasion. Inhibition of cathepsin L activity using CLIK-148 resulted in significantly increased CD8+ cytotoxicity. Of note, inhibition of cathepsins L and X in separate immune or tumor cells did not promote these functional changes. Together, our findings underlie the importance of tumor cell-immune cell interactions in the evaluation of the anti-cancer potential of cysteine cathepsin inhibitors.
    Vir: Cancer immunology and immunotherapy. - ISSN 0340-7004 (Vol. 69, 2020, str. 1869-1880)
    Vrsta gradiva - članek, sestavni del ; neleposlovje za odrasle
    Leto - 2020
    Jezik - angleški
    COBISS.SI-ID - 14118403

    Povezava(-e):

    https://link.springer.com/article/10.1007/s00262-020-02592-x
    DOI

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