Chapter 1 │ Page 23 advanced in vitro 3D models, including tumor spheroids and patient-derived organoids (PDOs), I assessed tumor kinetics, treatment cytotoxicity and synergy of the NTP-CDDP combination, followed by studying the immunological impact via DAMP and cyto/chemokine secretion. This in vitro data underlines the beneficial impact of incorporating NTP into conventional cisplatin therapy. Additionally, I demonstrated bona fide ICD induction and immune protection of NTP-CDDP via the gold standard vaccination assay in a syngeneic SCC7-C3H/HeN HNSCC mouse model. As protective immunity via vaccination is majorly driven by adaptive immunity, the goal of chapter 4 (research article) was to shed light on NTP’s immunomodulatory e ects in the context of innate immunity. By employing an unique approach, combining computational (contribution of drs. Pepijn Heirman) and experimental (my contribution) techniques, we explored the impact of NTP-induced oxidation of NK cell ligands on tumor cells. Molecular dynamics and umbrella sampling were employed to predict oxidative changes on the MHC-I complexes HLA-Cw4 and HLA-E, and showed no significant impact on the binding a inity of these markers to their corresponding NK cell receptor, which was also experimentally confirmed. Furthermore, I broadened the scope to other key ligands for NK cell reactivity, and demonstrated both rapid transient chemical interactions as well as triggering of a cascade of downstream cellular responses in NK ligands, including CD155, CD112, CD73 and stress proteins MICA/B, suggesting that NTP can reshape the tumor immune landscape to favor immune recognition. While the first three research chapters focused on several immunomodulatory aspects of NTP, the final chapter 5 (review article) broadens the perspective and describes the role of gap junctions (GJs) in cancer, immunology and therapy. As key mediators of intercellular communication, GJs are intricately linked to various biological processes, from regulating the intracellular redox balance to shaping immune reactions in the tumor microenvironment, and influencing therapeutic
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