Chapter 4 │ Page 145 understanding that NTP not only enhances tumor immunogenicity through the induction of immunogenic cancer cell death [14, 68], but also encompasses the modulation of crucial immune checkpoints within the tumor microenvironment. Hence, the compelling character of the highly reactive yet localized treatment profile of the complex mixture of species in NTP may render it an attractive candidate as a combination partner to bolster existing immune therapies facing critical challenges such as ligand shedding and immune evasion [66, 79, 80]. Nevertheless, further research is needed to fully understand the clinical relevance of our work, and to further investigate the e ects of NTP on NK cell-mediated cytotoxicity, for both HNSCC as well as other cancer types. Indeed, whether the observed NTP-induced modulation of the balance between inhibitory and activating ligands on tumor cells also translates into enhanced NK cell functionality remains to be validated, for instance through relevant co-culture experiments in HNSCC spheroids or, ideally, in an autologous patient-derived organoid (PDO) model. Additionally, within the context of this research scope, we are currently performing an in-depth analysis on the impact of oxidation-induced treatment e ects on the well-established immunological target PD-L1. These results will be particularly appealing given the significant clinical interest and the already proven therapeutic impact of targeting the PD-1/PD-L1 axis. 5. CONCLUSION Using both in silico and in vitro methods, we investigated the e ects of NTP treatment on di erent tumor-associated immune checkpoint ligands for NK cells. Taken together, our computational results indicate that MHC Class I molecules HLA-Cw4 and HLA-E are not significantly a ected by NTP-induced oxidative changes. Although the structure of the ligand-receptor complexes was altered, this did not result in a changed binding strength. Accordingly, we experimentally observed only minor alterations in the expression status of HLA-C and HLA-E, both
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