Abstract
Augmentation of natural killer (NK) cell cytotoxicity is one of the greatest challenges for cancer immunotherapy. Although histidine‐rich glycoprotein (HRG), a 75‐kDa glycoprotein with various immunomodulatory activities, reportedly elicits antitumor immunity, its effect on NK cell cytotoxicity is unclear. We assessed NK cell cytotoxicity against K562 cells. We also measured concentrations of cytokines and granzyme B in the cell supernatant. The proportion of CD56bright NK cells and NK cell surface PD‐1 expression was assessed with flow cytometry. The neutralizing effects of anti‐C‐type lectin‐like receptor (CLEC) 1B against HRG were also measured. NK cell morphological changes were analyzed via confocal microscopy. HRG significantly increased NK cell cytotoxicity against K562 cell lines. HRG also increased the release of granzyme B and the proportion of CD56bright NK cells. Further, HRG was able to decrease NK cell surface PD‐1 expression. The effects of HRG on NK cells were reversed with anti‐CLEC‐1B antibodies. Additionally, we confirmed NK cell nuclear morphology and F‐actin distribution, which are involved in the regulation of cytotoxic granule secretion. Because both PD‐1 and CLEC‐1B are associated with prognosis during malignancy, HRG incorporates these molecules to exert the antitumor immunity role. These facts indicate the potential of HRG to be a new target for cancer immunotherapy.
Highlights
One challenge of cancer immunotherapy is understanding the complex regulatory interactions between effector and target cells
Cells, and enhanced granzyme B secretion. This suggests that histidine-rich glycoprotein (HRG) functions to augment cytotoxic granule production in CD56dim cells, which primarily exert direct cytotoxic immunity,[43] while facilitating the transition of CD56dim to CD56bright cells
It was reported that CD56bright Natural killer (NK) cells are increased in the tumor microenvironment of several malignancies.[42,45]
Summary
One challenge of cancer immunotherapy is understanding the complex regulatory interactions between effector and target cells. Natural killer (NK) cells are unique innate lymphocytes that target viral infections and tumor cells Their functions as effector cells include cytokine production, such as interferon-gamma (IFN-γ), exocytosis of cytotoxic granules containing granzyme B, and direct killing of target cells through Fas ligands and tumor necrosis factor (TNF)-related apoptosis-inducing ligand pathways.[1,2,3,4,5,6] NK cells produce chemokines including RANTES (regulated on activation, normal T-cell expressed and secreted) that induce T-cell migration. The purpose of this study was to examine whether HRG enhances NK cell cytotoxicity and regulates cytokine production by these cells through the stimulation of specific receptors, focusing on revealing molecular and pathological associations with antitumor immunity
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