Division of Pathogenesis of Virus Associated Tumors
Prof. Dr. Dr. Henri-Jacques Delecluse
Electron micrograph of Epstein Barr virus particles bound to the surface of a human primary B cell.
© dkfz.de
The Epstein-Barr virus (EBV) infects the large majority of the population and is responsible for 1 to 2% of all cancers. EBV is also responsible for the development of infectious mononucleosis (IM), a frequent and potentially debilitating infectious syndrome. Recent epidemiological studies have demonstrated that EBV plays a major role in the development of auto-immune diseases, in particular multiple sclerosis. Finally, it is one of the last tumor viruses for which neither a preventative vaccine not a curative treatment is available.
Our projects aim at understanding how the virus induces these tumors. We previously found that the multiple microRNAs encoded by the virus modulate its oncogenic properties (Lin et al., PLoS Path 2015; Bernhardt et al., PLoS Path 2016; Haar et al., NAR 2016). We then moved our attention to the role of viral variants in the development of cancers (Li et al., Nature Microbiology 2019; Tsai et al., Cell reports 2015). Indeed, some EBV-associated tumors such as nasopharyngeal carcinoma and Burkitt’s lymphomas have a strikingly heterogeneous geographic distribution. We have shown that some of these differences can be explained by the infection with particular types of Epstein-Barr viruses.
Another interesting question is the contribution of lytic replication, the process that leads to the production of viruses, to cancer development and. We showed that the EBV infectious particles can deregulate the centrosome machinery and induce genetic instability (Shumilov et al., Nature Comm 2017). This newly identified cancer risk is independent of the viral genome and could significantly expand the range of diseases caused by the virus.
More recently, we have embarked on a collaborative project to study the role played by EBV in the development of the autoimmune disease multiple sclerosis. We will study the interactions between the virus and the host, with a focus on the role of polymorphisms, both viral and cellular, and how they influence the immune response against the virus.
We have also developed a new type of immunotherapy that is based on antibodies that recognize surface proteins on tumor cells that are combined with viral antigens. The antibody moiety bids to the tumor cells, allowing the internalization of the viral antigens. These in turn are loaded on MHC class II molecules, allowing recognition of the tumor cells by T cells specific for the viral antigen. These antigen-loaded antibodies, or AgAbs have demonstrated their efficacy in a model of lymphoma in vitro. Since then we have obtained evidence of efficacy and safety in an animal model of acute myeloid leukemia.
FUTURE OUTLOOK
While we will continue our projects on the molecular mechanisms of EBV-induced cancer, we will develop a new project on the role of EBV in the development of multiple sclerosis and other autoimmune diseases. Another priority will be the further development of immunotherapeutic strategies based on antigen-loaded antibodies.
