Physical Plasma-Treated Skin Cancer Cells Amplify Tumor Cytotoxicity of Human Natural Killer (NK) Cells

Abstract

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.

Multimodal Imaging Techniques to Evaluate the Anticancer Effect of Cold Atmospheric Pressure Plasma

“…Along those lines, we have previously shown increased myeloid and lymphoid immuno-infiltration into gas plasma-treated syngeneic B16 melanomas in vivo [47], while checkpoint immunotherapy augmented therapeutic efficacy in the similar tumour model, but using another plasma device [48]. An in vitro study using the same two tumour cell lines showed that not only the adaptive immune system mediates anti-cancer effects after CAP treatment, but also innate immune cells, such as NK cells, lead to significantly higher apoptosis of tumour cells, due to expression modulation of activating and inhibiting receptors on tumour cells after CAP treatment [49].…”

Tumor cytotoxicity and immunogenicity of a novel V-jet neon plasma source compared to the kINPen

“…The relevance of this cross-species approach is underlined by DC activation being triggered via the binding of immune-stimulatory molecules to evolutionarily conserved pattern recognition receptors such as toll-like receptors that only differ slightly in structure and subsequent signaling pathways across species 80,81 . Effects of plasma-derived species on myeloid cells such as DCs [82][83][84] , macrophages 85,86 as well as innate lymphocytes 87 was suggested before already.To gain evidence of the tumor treatment regimes' ability to induce DC maturation, we characterized the expression of reliable maturation www.nature.com/scientificreports/ markers on DCs. We found kINPen but not V jet plasma-treated tumor cells to promote dendritic cell maturation and tumor cell phagocytosis.…”

Murine Macrophages Modulate Their Inflammatory Profile in Response to Gas Plasma-Inactivated Pancreatic Cancer Cells

“…This may also affect other targets of the TME, such as thiols [ 57 , 58 , 59 ] and extracellular matrix hyaluron [ 60 ], that upon plasma treatment were recently identified to show disrupted binding to its receptor CD44 [ 61 ]. The second is long-term effects on the expression levels of immune-relevant ligands and receptors, as we and others have reported recently [ 54 , 62 , 63 , 64 , 65 , 66 ]. Importantly, both events may combine during gas plasma exposure of cancer tissue to promote antitumor immunity [ 67 , 68 ].…”