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Updated: Aug 2, 2025
Assessment of Human Natural Killer Cell Events Driven by FcγRIIIa Engagement in the Presence of Therapeutic Antibodies
Published on: May 22, 2020
IFN-β activates cytotoxic function of human natural killer cells toward IL-27 and poly(I:C) stimulated PC3 and DU145
Olena Kourko1, Lindsey G Hawke1, Mark L Ormiston1
1Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
Abstract:
Natural killer (NK) cell phenotype and function are altered in patients with prostate cancer, and increased NK cell activity is associated with a better prognosis in patients with disease. For patients with advanced stage prostate cancer, immunotherapies are a promising approach when standard treatment options have been exhausted. With the rapid emergence of NK cell-based therapies, it is important to understand the mechanisms by which NK cells can be triggered to kill cancer cells that have developed immune-evasive strategies. Altering the cytokine profiles of advanced prostate cancer cells may be an area to explore when considering ways in which NK cell activation can be modulated. We have previously demonstrated that combining the cytokine, IL-27, with TLR3 agonist, poly(I:C), changes cytokine secretion in the advanced prostate cancer models, PC3 and DU145 cells. Herein, we extend our previous work to study the effect of primary human NK cells on prostate cancer cell death in an in vitro co-culture model. Stimulating PC3 and DU145 cells with IL-27 and poly(I:C) induced IFN-β secretion, which was required for activation of primary human NK cells to kill these stimulated prostate cancer cells. PC3 cells were more sensitized to NK cell-mediated killing when compared to DU145 cells, which was attributed to differential levels of IFN-β produced in response to stimulation with IL-27 and poly(I:C). IFN-β increased granzyme B secretion and membrane-bound TRAIL expression by co-cultured NK cells. We further demonstrated that these NK cells killed PC3 cells in a partially TRAIL-dependent manner. This work provides mechanistic insight into how the cytotoxic function of NK cells can be improved to target cancer cells.
Insights
Natural killer (NK) cells can be activated to kill prostate cancer cells by altering their cytokine profiles. This research shows how interferon-beta (IFN-β) enhances NK cell-mediated killing of cancer cells.
Area of Science:
- Immunology
- Cancer Biology
- Prostate Cancer Research
Background:
- Natural killer (NK) cell function is altered in prostate cancer patients, with higher NK cell activity correlating with better prognosis.
- Immunotherapies, including NK cell-based approaches, offer promise for advanced prostate cancer.
- Understanding NK cell activation mechanisms is crucial for overcoming cancer's immune-evasive strategies.
Purpose of the Study:
- To investigate the effect of primary human NK cells on prostate cancer cell death.
- To explore how modulating cytokine profiles, specifically using IL-27 and poly(I:C), enhances NK cell-mediated cytotoxicity.
- To elucidate the role of interferon-beta (IFN-β) in NK cell activation against prostate cancer cells.
Main Methods:
- Utilized an in vitro co-culture model with primary human NK cells and advanced prostate cancer cell lines (PC3 and DU145).
- Stimulated prostate cancer cells with Interleukin-27 (IL-27) and poly(I:C) to assess cytokine secretion and NK cell activation.
- Measured NK cell-mediated killing, IFN-β secretion, granzyme B release, and membrane-bound TRAIL expression.
Main Results:
- Stimulation with IL-27 and poly(I:C) induced IFN-β secretion in PC3 and DU145 cells, which was essential for NK cell activation.
- PC3 cells showed greater sensitization to NK cell killing than DU145 cells, linked to differential IFN-β production.
- IFN-β enhanced granzyme B secretion and membrane-bound TRAIL expression in NK cells, contributing to cancer cell death, partially via TRAIL.
Conclusions:
- Interferon-beta (IFN-β) plays a critical role in activating NK cells to kill prostate cancer cells.
- Combining IL-27 and poly(I:C) shows potential for enhancing NK cell-mediated anti-cancer activity.
- This study provides mechanistic insights into improving NK cell cytotoxic function against prostate cancer.
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