OX40-mediated immune regulation in viral hepatitis and hepatocellular carcinoma

• Applicant: Professor Dr. Tobias Böttler
• Subject Area: Gastroenterology
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 279710275

Persistent infections with hepatitis viruses are major risk factors for progressive liver disease causing severe complications such as chronic liver failure and hepatocellular carcinoma (HCC) in millions of chronically infected individuals worldwide. Current therapies for chronic viral hepatitis and HCC have major limitations although great advances have been made in the development of novel therapeutics against HCV infection in recent years. However, the pressing need for a preventive vaccine persists and new therapeutic strategies to tackle chronic HBV infection and liver cancer are desperately needed as current therapies fail to offer a cure for affected individuals.T cell based immunotherapy has been suggested to be a promising approach to tackle HBV in chronically infected patients and to treat malignancies such as HCC. Indeed, cancer-immunotherapy has been selected as breakthrough-of-the-year 2013 by SCIENCE magazine. In order to establish protocols for T cell based immunotherapies, a detailed knowledge of the virus-specific (and tumor-specific) T cell responses is of critical importance. Indeed, the immunologic determinants that govern the clinical outcome of viral hepatitis remain incompletely understood and require further investigation. The last decade of research has provided insights on T cell dysfunctions in the setting of chronic viral hepatitis and HCC. And while great efforts have been made in the identification and characterization of the inhibitory pathways that negatively regulate T cell responses, pathways that can positively regulate T cell responses in these contexts have not been comprehensively analyzed. Thus, in order to address this shortcoming, we propose to identify the pathways that bear the potential to rescue the dysfunctional immune responses during persistent viral hepatitis as well as HCC. Importantly, the applicant could demonstrate in a mouse model of chronic viral that signals through the TNF-receptor superfamily member OX40 are crucial players in maintaining functional immune responses. However, whether OX40 actively sustains T cell responses in viral hepatitis in humans or whether OX40 stimulation has the ability to enhance virus-specific or tumor-specific T cell responses in HBV, HCV or HCC has never been analyzed.Thus, a detailed analysis of the co-stimulatory OX40 molecule and its related TNF-receptor family members and their role in regulating T cell responses is required in order to gain a deeper understanding of how adaptive immunity is regulated in the setting of chronic viral hepatitis and hepatocellular carcinoma. Such knowledge will be vital for the establishment of immunotherapeutic approaches in HBV-infection and HCC.

• DFG Programme: Research Grants