INVESTIGATION INTO THE MODULATION OF IMMUNE CELLS BY METALLODRUGS

Abstract

Modulating the immune system to clinically achieve the relevant tumoricidal outcomes is a longstanding goal. In this thesis, we discussed the application of Platinum-based chemodrugs in strategies to induce anticancer immunomodulation using macrophage model. The first strategy aimed to target macrophages directly (i.e. a macrophage-centric approach), in which the ability of the complexes on stimulating M1 tumoricidal phenotype via exerting TLR2/4-dependent NF-𝜅B activation was examined. The further investigation on the activation of the hit compound cisplatin was then performed. The second strategy was to target immunogenicity of tumours (i.e. a tumour-centric approach), which aimed to evaluate the indirect modulation of Pt-based drugs on macrophages’ activity via triggering tumour immunogenic cell death (ICD). The mechanism of action of the hit complex, phenanthriplatin, was further investigated. We also extended the list of other potential metal-based complexes as ICD inducers by elucidating the underlying working mechanism of gold(I) complexes inducing ER stress.