Chapter 6 │ Page 206 as a good or even synergistic combination partner for radiotherapy, targeted therapy and other chemotherapy [28-30]. Immunotherapeutic developments have primarily focused on adaptive immunity, with special interest in the most potent antigen-presenting cells, DCs, and cytotoxic T lymphocytes [31-34]. However, innate immunity can also play a valuable cytotoxic role, a concept that has now been adopted, illustrated by rapidly emerging natural killer (NK) cell-based therapies [35-37]. An area of growing expertise in our laboratory is the development of chimeric antigen receptor (CAR) NK cell therapies, considered as a promising o -the-shelf cellular treatment option [37-39]. Expertise has taught us that one of the major challenges is e ective tumor infiltration, which is pivotal for solid tumors with a significant physical and immune suppressive barrier [40-42]. In this regard, studies have shown that tumor debulking prior to cellular therapy can enhance treatment e icacy [43, 44]. Hence, although fully unexplored, NTP may present an intriguing opportunity to first reduce tumor mass locally, to give cell therapy a better chance of success. In addition to this rather long-term combination potential to enhance CAR-based therapies, more immediate steps can already been taken to explore the role of NTP in NK cell-mediated immunity. Research chapter 4 of this dissertation specifically aimed to investigate how NTP might directly enhance NK cell-mediated anti-tumor responses by modulating the immunophenotype of the tumor surface. Certain molecular e ects are challenging to capture through experimental methods alone, so we adopted a multidisciplinary approach, integrating computational and experimental methods. Our lab has been a pioneer in this, previously demonstrating NTP’s disruptive interference on two tumor-promoting signaling axes, namely CD47- SIRPα[15] and CD47- hyaluronan [45] via this research strategy. Here, we demonstrated that NTP-induced oxidation immediately impacted several key inhibitory ligands, including TIGIT axis ligands and the checkpoint CD73, which
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