Pathogenesis of virus-associated tumours

Research

Our research projects aim at understanding the pathogenesis of cancers caused by an infection with the Epstein-Barr virus (EBV) and at developing vaccination strategies to prevent them. We have also developed a new immunotherapeutic approach that uses EBV antigens to induce an immune response against B cell lymphomas.

The Epstein-Barr virus (EBV) induces cancers that are characterized both by their diversity and their geographic heterogeneous distribution. EBV is associated with malignant lymphomas such as Hodgkin lymphoma, Burkitt’s lymphoma, large cell lymphoma and T cell lymphomas. It also induces nasopharyngeal carcinomas and a subset of gastric carcinomas. Moreover, some of these tumors are found with an increased frequency in specific parts of the world. These include nasopharyngeal carcinomas in South-East Asia and Burkitt’s lymphoma in Equatorial regions. We have proposed that these differences result from infection with different EBV strains that are unequally distributed around the world. This hypothesis is supported by our observation that EBVs isolated from nasopharyngeal or gastric carcinomas have a much stronger tropism for epithelial cells than viruses found in lymphomas (Tsai et al Cell reports 2015, Tsai et al Oncotarget 2017). We will pursue these investigations by studying the properties of viruses isolated from patients with EBV-associated diseases with the aim of identifying specific properties. We currently focus on viruses isolated from transplant recipients who frequently suffer from EBV-associated diseases (see project 3). These projects require classical molecular Virology methods, associated with large-scale genomics and Bioinformatics approaches.

Epidemiological studies have shown that individuals who have very high antibody titres against EBV proteins involved in virus lytic replication, the process that leads to new virus progeny, have an increased risk of developing nasopharyngeal carcinoma. We have identified EBV strains that induce strong lytic replication and used them to study the contribution of lytic replication to cancer development (Tsai et al Cell reports 2015). By comparing the properties of this virus with those of a mutant that cannot replicate, we have found that the replicating viruses are more tumorigenic (Shumilov, Tsai et al. Nature comm 2017). We found that the virus particles themselves induce centrosome overduplication and more generally genomic instability (See project 1). Importantly, these abnormalities can be induced by virus-like particles and are independent of the viral DNA. As the majority of the population is infected by EBV, this identifies a new risk factor for cancer development. 

We also study the molecular mechanisms that lead to neoplastic transformation. To sunderstand the contribution of viral microRNAs to the development of cancer, we generate mutants that lack all or only part of these non-coding RNAs and compare their properties with those of wild type viruses (Lin et al, PLoS Path 2015, Bernhardt et al, PLoS Path 2016, Haar et al. NAR 2016). The mutants are constructed with genetic systems that use homologous recombination to allow modification of every single base pair within the viral genome.

We have generated EBV mutants that could be potentially used as vaccines because they produce large amounts of viral DNA-free virus-like particles (VLPs) (See project 2). These particles elicit a strong immune response, yet have lost any pathogenic potential (Pavlova et al J Virol 2013).

Although EBV is a tumor virus, only a minority of infected individuals develop tumors. This is due to a large extent to the ability of the immune system to control EBV-infected cells. This implies that the majority of the population can mount a very potent immune response against the virus. We have designed a new immunotherapeutic strategy that is based on this observation and in which T cells specific to EBV epitopes are used to kill tumor cells (Yu, Ilecka et al. Blood 2015). This strategy uses a new type of armed antibody that consists of fusion proteins between antibodies and EBV epitopes. These chimeric antibodies bind to tumor cells, lead to efficient and specific presentation of EBV-specific antigens at their surface and to their killing by EBV-specific T cells (See project 4).

Research projects

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