Characterization of the metabolic adaptions in the immune infiltrate during the transition from non alcoholic steatohepatitis (NASH) to hepatocellular carcinomas (HCC)

• Applicant: Dr. Johannes Schwenck
• Subject Area: Endocrinology, Diabetology, Metabolism ; Gastroenterology ; Hematology, Oncology ; Immunology
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 456311466

The liver is the central metabolic organ in the human body and therefore highly affected by the western, sedentary life style. Malnutrition with a high caloric diet induces a hepatic steatosis and subsequently an inflammatory process called “non alcoholic steatohepatitis” (NASH). This is critical as the cases of metabolic disorders are rapidly increasing worldwide. NASH can lead to the development of hepatocellular carcinomas (HCC), a cancer with very limited treatment options. The liver tissue exhibits a special immune system, because foreign substances continuously coming up from the gastrointestinal tract have to be tolerated. A complex interplay between resident liver cells as well as immigrating immune cells is necessary to achieve this special immune environment, which is not fully understood yet.In recent years the evidence was growing that metabolic factors are crucially interfering with the immune system and therefore influence inflammatory diseases, development of cancer and the immune response against cancer. Different types of immune cells are highly sensitive to metabolic influences, because they prefer different types of nutrients to work properly. In tumors it was already proven that the competition of tumor cells and immune cells for different nutrients is massively influencing the tumor immune response. The mechanisms how resident and infiltrating immune cells adapt to the metabolic alterations in NASH and how this impacts the HCC development are largely unknown to date. In vivo imaging is able to measure macroscopic changes in the organ metabolism and to track the homing of specific immune cell populations in the liver but is lacking single cell resolution and is unable to investigate several immune cell populations in parallel. Therefore, in this project different techniques to characterize the metabolic processes on a cellular level will be facilitated to explore the different metabolic adaptions of the immune infiltrate in the steatotic environment of NASH liver tissue.Thus, we will unravel the timepoints of relevant metabolic changes during the course of the disease. Furthermore, we aim to investigate how this metabolic adaptions are affecting the development of NASH induced HCC and whether this could be influenced by therapeutic approaches.On the long run, these findings will help to uncover new insights into the pathogenesis of NASH driven HCC, which might improve the clinical diagnostic and therapy.

• DFG Programme: WBP Fellowship
• International Connection: Switzerland
• Host: Professor Ping-Chih Ho, Ph.D.