Team: Dr. Yazid Resheq, Ann-Katrin Menzner
Our young group has strong interest in the role of hydrogen-peroxide for function and differentiation of human monocytic cells through-out tumour-rejection. Importantly, various studies indicate that hydrogen-peroxide which is produced in high quantities in case of increased metabolic activity may serve as a second messenger i.e. suppressing effector-T-cells consecutively preventing tumour-rejection (so called tumour-immune-escape). However, such reactive-oxygen-species are equally harmful for malignant cells leading to an enhanced expression of detoxifying enzymes such as catalase in tumours themselves. In a pilot-study we were able to show for the first time that hydrogen-peroxide is equally important for differentiation and function of human monocytic cells hence undermining the complex nature of hydrogen-peroxide: Using hepatic stellate cells we were able to demonstrate that contact-dependent depletion of hydrogen-peroxide leads to a differentiation of human monocytes to myeloid-derived suppressor cells (MDSCs) which are renounced for their immunosuppressive activity in various malignant diseases. Currently, we are analysing to what extends tumours may use such mechanisms in order to achieve a favourable microenvironment, i.e. by inducing tolerogenic dendritic cells.
Additionally, our group focuses on the influence of tumours on their surrounding vessels and the consecutive impact on transendothelial immune-cell-accumulation as potential novel mechanism of tumour-immune-escape. Herein, we have established a strong cooperation with the MBT and OICE where we use so called flow-based adhesion assays which allow an accurate visualisation of the complex transmigration cascade using primary tumour-derived endothelial cells. Of note, these assays are capable to visualise every critical step of immune-cell-trafficking across the endothelial barrier in real-time hence allowing a so far unpreceded depth in analysing transendothelial migration. In one of our most recent studies, for example, we were able to demonstrate that hepatic sinusoidal endothelial cells are capable to license human inflammatory monocytes to reverse transmigrate thus limiting inflammation in the hepatic compartment. Our current projects focus on completely automating this technique and, in close cooperation with the local department of urology, to analyse to what extend renal cell carcinoma impacts on its peritumoral angiogenesis and consecutively on transendothelial immune-cell-accumulation into peritumoral tissue.