Chapter 4 │ Page 144 treatment modulated CD47 expression di erently across the cell lines (Supplementary Figure 3). The fact that di erent behaviors can be seen immediately after treatment indicates that biological e ects beyond purely the chemical protein alterations are at play. Further studies investigating underlying mechanisms (e.g., genetic profile, tumor subsite, disease stage) are necessary to fully elucidate the implications and biological relevance of these observations. Furthermore, in-depth analysis of the chemical alterations in protein structure using mass spectrometry could be a valuable subsequent step to shed light on these observations, and potentially unravel additional post-translational modifications relevant for instant ligand reduction (e.g. nitrosylation). The results presented in this work build upon previous work performed in our lab combining experimental and computational methods [31, 32] and broaden our knowledge on crucial aspects of the interaction between NTP, cancer cells, and immune cells. Indeed, our research on the cytotoxic capacities of NK cells following NTP application has previously demonstrated enhanced NK cellmediated killing in both in vitro and in vivo melanoma models [18, 22]; Lin et al. demonstrated in an in vivo mouse model that while the number of infiltrating T and NK cells remained unchanged, their cytotoxic activity appeared enhanced, as evidenced by increased granzyme B levels. In vitro co-culture experiments by Clemen et al. showed that plasma-treated melanoma cells enhanced NK cellmediated cytotoxicity, potentially induced by changes in the expression of selected NK ligands and secretory profile. The objective of this manuscript was to build further on these functional observations, while specifically highlighting the e ects of NTP on key tumor cell-NK cell signaling axes. Our results demonstrate a significant impact of NTP application on di erent inhibitory and activating ligands and pathways, critical for NK cell functioning, but also indicate that these e ects are dependent on both the specific protein and cell type. This data corroborates the robust immunomodulatory capabilities of NTP. Specifically, it broadens the
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