Abstract
Altered sialic acid processing that leads to upregulation of cell surface sialylation is recognized as a key change in malignant tissue glycosylation. This cancer-associated hypersialylation directly impacts the signaling interactions between tumor cells and their surrounding microenvironment, especially the interactions mediated by immune cell surface sialic acid-binding immunoglobulin-like lectins (Siglecs) to relay inhibitory signals for cytotoxicity. First, we obtained a Siglec-7neg NK-92MI cell line, NK-92MI-S7N, by separating a group of Siglec-7neg cell population from an eight-month-long-term NK-92MI in vitro culture by fluorescence-activated cell sorting (FACS). The effect of Siglec-7 loss on NK-92MI-S7N cells was characterized by the cell morphology, proliferation, and cytotoxic activity via FACS, MTS assay, cytotoxic assay, and natural killer (NK) degranulation assay. We found the expression levels of Siglec-7 in NK-92MI were negatively correlated with NK cytotoxicity against leukemia cells. This NK-92MI-S7N cell not only shared very similar phenotypes with its parental cells but also possessed a high and sustainable killing activity. Furthermore, this Siglec-7neg NK line was unexpectedly capable of eliminating a NK-92MI-resistant leukemia cell, THP-1, through enhancing the effector-target interaction. In this study, a NK cell line with high and sustainable cytotoxicity was established and this cell may provide a potential application in NK-based treatment for leukemia patients.
Highlights
Natural killer (NK) cells are a group of innate lymphocytes, comprising 5–20% of human peripheral blood lymphoid cells, and serve as an important constituent in host protection against viral infections and immune malignancy surveillance [1,2]
NK-92MI cell is known for its application in clinical trials as the first NK cell line used in NK-mediated immunotherapy against cancer and leukemia [38,39,40], the details of its regulatory mechanism for such cytotoxicity response are still under investigation
By non-radioactive cytotoxicity assay, the killing activities were significantly lower in the NK-92MI-S against three selected leukemia cell lines, at effector:target (E:T) ratios from 1:1 to 10:1, as opposed to those observed in parental NK-92MI (Figure 1A–C)
Summary
Natural killer (NK) cells are a group of innate lymphocytes, comprising 5–20% of human peripheral blood lymphoid cells, and serve as an important constituent in host protection against viral infections and immune malignancy surveillance [1,2]. These cells can recognize and kill aberrant cells without preliminary antigen sensitization. Diminution or absence of cell surface MHC-I molecules, resulting from viral infections or tumor transformations, leads to a reduced overall inhibitory signal, thereby activating NK cells to eliminate those missing-self targets [8,9]. NK-cell cytotoxicity is achieved by degranulation of these accumulated granules toward the direction of the engaged target
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