Pathogenesis of Virus Associated Tumors

Multiple sclerosis (MS) is a neurological disease in which the immune system irreversibly damages the myelin layer in the brain and spinal cord, potentially leading to serious consequences such as paralysis or severe visual impairment. Recent work by Bjornevik and colleagues (Bjornevik et al., Science 2022) has demonstrated the causal link between EBV infection and the development of multiple sclerosis, confirming previous reports that showed infectious mononucleosis as a risk factor for MS. However, despite the many proposed roles played by EBV in the pathogenesis of this neurodegenerative autoimmune condition, limited evidence is currently available.

Our laboratory, in partnership with other 10 research groups across Europe, has received funding in the frame of the Horizon Europe Programme to shed new light on how EBV interaction with the host can promote the development of MS. The BEHIND MS Consortium, with our group as coordinator, by bringing together complementary expertise, will investigate in vitro, ex vivo, and in vivo the mechanisms underlying the pathogenic role of EBV in multiple sclerosis, with the goal of identifying new druggable therapeutic targets and biomarkers to improve diagnose, staging and treatment of this yet-incurable disease.

Patients with an immunodeficiency, and in particular transplant recipients, have a reduced ability to control infectious agents. In the presence of a diminished functional T cell response, a substantial proportion of individuals who were previously infected with EBV cannot prevent infected B cells from resuming proliferation (Figure 1). Transplant recipients, in particular children, who undergo primary infection whilst already under immunosuppressive treatment carry an even higher risk of EBV-associated diseases like post-transplant lymphoproliferative disorders (PTLD). We have previously studied the viral strains that are found in EBV-associated nasopharyngeal carcinomas and gastric carcinomas and found that these strains exhibit specific properties (Tsai et al. Cell reports 2013, Shumilov, Tsai et al Nature comm. 2017). We are now exploring the hypothesis that the risk of PTLD is linked with infections with EBV strains endowed with higher transforming abilities. We have recruited a collective of patients with EBV reactivation after transplantation and have established cell lines infected with EBV from their peripheral blood. We aim to study multiple parameters such as viral and cellular protein implicated in EBV-mediated transformation and microRNA expression in primary cells and in the cell lines that were established from these patients.

This project results from a close cooperation with the Kidney Center Heidelberg e.v., the Department of Haematology as well as the Institute of Virology from the University of Heidelberg.

Acute myeloid leukemia (AML) accounts for 80% of acute leukemia cases in adults and results from the accumulation of immature malignant myeloid cells at the expense of healthy differentiated counterparts. The treatment options for AML remain limited. While a moderate therapy success has been observed in patients below the age of 65, about 70% of older patients succumb to the disease within one year after diagnosis. Therefore, the search for more therapeutic options in AML is imperative.

Our laboratory has developed a platform for efficient delivery of immunodominant viral epitopes to tumor cells. The approach is based on antigen-armed antibodies (AgAbs) that carry antigens from the Epstein-Barr virus (EBV). With the help of this strategy, malignant cells become visible for the immune system and are targeted by EBV-specific CD4+ cytotoxic T cells. Indeed, AgAbs bind to surface molecules expressed by the malignant cells and provoke receptor-mediated endocytosis. As a result, viral peptides included in the AgAbs are shuttled into the endosomal compartments of the target cells, where the epitopes can be processed for MHC class II-restricted presentation on the cell surface. In EBV-positive individuals, circulating memory virus-specific cytotoxic CD4+ T cells recognize the MHCII-bound peptides on the surface of tumor cells and mediate cell lysis.

We have developed AgAbs that specifically target AML and leukemia stem cells. This approach makes sense because a high percentage of AML cells express functional MHC-II molecules and up-regulate several specific membrane receptors. Our preliminary experiments suggest that the AgAb strategy in AML is promising. Indeed, AgAbs can eliminate primary AML cells in vitro and ex vivo. Moreover, this therapeutic approach conferred a strong survival advantage in a murine AML model.