Abstract
Simple SummaryNatural killer (NK)-cells are known to have antitumor potential. Cold physical plasma generates ROS exogenously to be utilized as a novel anticancer agent, especially in skin cancer. However, it is unknown whether plasma-treated skin cancer cells promote or inhibit NK-cell-mediated toxicity. To this end, we analyzed NK-cell-activating receptors on plasma-treated skin cancer cells and demonstrated an enhanced NK-cell activity augmenting tumor cell death upon plasma treatment.Skin cancers have the highest prevalence of all human cancers, with the most lethal forms being squamous cell carcinoma and malignant melanoma. Besides the conventional local treatment approaches like surgery and radiotherapy, cold physical plasmas are emerging anticancer tools. Plasma technology is used as a therapeutic agent by generating reactive oxygen species (ROS). Evidence shows that inflammation and adaptive immunity are involved in cancer-reducing effects of plasma treatment, but the role of innate immune cells is still unclear. Natural killer (NK)-cells interact with target cells via activating and inhibiting surface receptors and kill in case of dominating activating signals. In this study, we investigated the effect of cold physical plasma (kINPen) on two skin cancer cell lines (A375 and A431), with non-malignant HaCaT keratinocytes as control, and identified a plasma treatment time-dependent toxicity that was more pronounced in the cancer cells. Plasma treatment also modulated the expression of activating and inhibiting receptors more profoundly in skin cancer cells compared to HaCaT cells, leading to significantly higher NK-cell killing rates in the tumor cells. Together with increased pro-inflammatory mediators such as IL-6 and IL-8, we conclude that plasma treatment spurs stress responses in skin cancer cells, eventually augmenting NK-cell activity.
Highlights
The immune system protects the body from pathogens and the damage they inflict
We aimed at investigating the consequences of plasma-inactivated tumor cells on Natural killer (NK)-cell activity
We aimed at investigating the consequences of plasma-inactivated tumor cells on NK-cell decreased the metabolic activity of the skin cancer cell lines A431 (Figure 1c) and
Summary
The immune system protects the body from pathogens and the damage they inflict. It is classically divided into innate immunity and adaptive immunity. Physical plasma treatment was shown to promote cell death in several tumor cell types, including skin cancer [11,12,13,14]. We have previously shown an increased surface expression or release of calreticulin, ATP, and heat-shock proteins in plasma-treated tumor cells [15,16,17] These molecules are important for triggering the activation of innate immune cells and the immunogenic cancer cell death (ICD) [18]. This can lead to enhanced immuno-protection upon plasma treatment in vivo [19,20,21]. Using HaCaT keratinocytes as a non-malignant control cell line, we identified plasma treatment to potentiate NK-cell-mediated inactivation of tumor cells and to spur the release of inflammatory mediators
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