3. Thema: Modulating Macrophages and Platelets in Liver Cancer and Infection
Supervisors:
Dominik Siegl
Institut für Translationale Immunologie
Martina Casari
Centrum für Thrombose und Hämostase (CTH)
Research Topic of Martina's and Dominik's Project:
Hepatocellular carcinoma (HCC) ranks among the five most prevalent cancers worldwide and has only limited treatment options. Tumor-associated M2-type macrophages (TAMs) actively suppress an effective immune response to HCC. Platelets interact with macrophages to regulate their polarization and inflammatory responses in cancer and infection. We plan to characterize this interaction and aim at developing novel targeted therapeutics to effectively treat these conditions with combined macrophage repolarizing and platelet modulating interventions in vitro and in HCC mouse models in vivo. The effect and safety of these interventions will be assessed in liver infection models.
Background:
Every day, our body has to deal with many different pathogens (e.g. bacteria, viruses). Fortunately, we do not get sick every time we come in contact with pathogens, because we are equipped with a highly effective and complex immune system. Our immune system plays a role not only in detecting and eliminating external threats, but also in diseases developing within the body, such as autoimmune diseases, allergies or cancer. In the first two examples, the immune system “overshoots”, tries to fight harmless substances (like pollen in an allergy) or attacks its own body. Cancer cells are often recognized and eliminated by the immune system at an early stage. If this is not the case, these cells can grow uncontrollably and form tumors. In this state, the immune system may eliminate some of the cancer cells but it is usually unable to eliminate the tumor, mainly because the tumor begins to interact with some immune cells and reprogram them for its own benefit via signaling molecules, alteration of the tumor microenvironment (TME), and so on. One of these cell types in which we are particularly interested are macrophages. Macrophages are cells of the so called innate immune system. They can kill microorganisms, are necessary for a healthy tissue architecture because they remove dead cells, and are also highly important for the stimulation of other immune cells. In the tumor microenvironment, they are often reprogrammed into a state of so-called “M2 macrophages” that support the tumor, resulting in an insufficient immune response. However, it is possible to change their phenotype to an anti-cancer state (M1 type). Therefore, we are interested in the reprogramming of the M2s to M1 macrophages.
Project:
During the project you will learn how to generate macrophages from bone marrow (stem) cells, how to culture murine macrophages and how to polarize them into different phenotypes (M1 vs. M2). You will repolarize them using specific drugs (M2 to M1), with or without platelets, and learn how to characterize them using state-of-the-art methods such as flow cytometry, quantitative polymerase chain reaction (qPCR) and (fluorescence) microscopy.
