Immune cells in thiosemicarbazone anticancer activity

During the last years, it became more and more apparent that the immune system greatly affects the activity of many anticancer therapies, often resulting in enhanced therapy efficacy. The drug class of anticancer thiosemicarbazones (TSCs) has been studied in several clinical trials including a promising combination with the regularly used chemotherapy cisplatin and radiation therapy, which are both known to modulate the immune system in a favorable way. However, no investigations regarding the effect of TSCs on the anticancer immune response were conducted so far. Consequently, the aim of this study is to assess the role of the immune system in TSC activity. Our preliminary results already indicated that especially the adaptive arm of the immune system is crucial for TSC anticancer activity. Therefore, in this study, the underlying mechanisms will be elaborated in more detail. In addition, we will investigate whether the clinical combination of TSCs with cisplatin results in an even higher enhancement of the anticancer immune response. To this end, we will employ diverse high-end techniques in a translational scientific network setting. An important part of the project will be the single cell analysis by flow cytometry of immune cells either located in (TSC-treated) tumor tissue or isolated from cell co-cultures with tumor cells. To that end, the identification markers on the surface of the immune cells are labeled with specific fluorescent antibodies to divide them for their different roles and activation states. The labels of each single cell will then be excited by lasers and fluorescence intensities will be measured by the sensitive detectors of flow cytometer. This will give us an overview of the changes occurring in tumor-associated immune cells during TSC therapy. Furthermore, immune cell migration and tumor infiltration will be observed in real-time. For this purpose, a genetically modified model system will be used that possesses immune cells which can be stimulated to produce bioluminescence. For more in-depth analysis, cell culture and biochemical methods will be applied to illuminate the molecular mechanism by which TSCs modulate the immune system. The project will enable us to elucidate the, until now not investigated, role of the immune system in the anticancer activity of clinically developed TSCs, which will result in a better understanding of the mechanism of these anticancer compounds as well as enable the design of improved therapy strategies.