Epstein-Barr virus: Mechanisms of cancer development decoded - Pioneering research with peptides from peptides&elephants

Over 90 percent of adults worldwide are infected with the Epstein-Barr virus (EBV). The virus belongs to the herpes viruses and stays in the body for a lifetime. It causes glandular fever, but it can also develop into Hodgkin's or non-Hodgkin's lymphoma after several years of reactivations. The circumstances under which this happens have not yet been clarified.

Scientists led by Hannes Vietzen and Elisabeth Puchhammer-Stöckl from the Center for Virology at the Medical University of Vienna, Austria, have examined the mechanisms more closely and published their results in the specialist journal Frontiers in Immunologie.* The scientists suspected an immune escape mechanism, in which the LMP-1 peptide of the Epstein-Barr virus plays a central role. Peptides&elephants synthesized the LMP-1 peptide for the research group's investigations. The polymorphic peptide is produced by the Epstein-Barr virus while it persists in the infected cells.

The LMP-1 peptide causes the infected cells to place more leukocyte antigen E (HLA-E) on their surface. The natural killer cells (NK) recognize the leukocyte antigen E and adjust their activity accordingly: If the natural killer cells bind to the leukocyte antigen E via their NKG2A receptor, they classify the cells as healthy and reduce their activity. If, on the other hand, the NKG2C receptor comes into play, the natural killer cells increase their activity. But in what way is this significant for the development of cancer?

Special LMP-1 and HLA-E variants meet impaired NK receptors

Vietzen and colleagues recruited 63 patients with EBV-positive Hodgkin's and non-Hodgkin's lymphoma for their study and 192 controls. In the controls, the Epstein-Barr virus had reactivated several times, but no lymphoma had developed. The scientists examined blood samples from the subjects using genetic association approaches and functional in vitro natural killer cell assays.

The results were groundbreaking: in the lymphoma patients, only those strains of the Epstein-Barr virus reactivated that formed the high-affin LMP-1 GGDPHLPTL peptide variant. In addition, the infected cells of the patients had significantly more leukocyte antigen E of the high-expressing variant *0103/0103 on their surface. The combination of both variants efficiently inhibited the activity of natural killer cells that possess the NKG2A receptor.
At the same time, the activity of the natural killer cells with NKG2C receptor was impaired in the lymphoma patients. For genetic reasons, about a third of the European population forms fewer or no NKG2C receptors on their natural killer cells. Those affected lack immune-stimulation via leukocyte antigen E.

Monoclonal antibodies prevent immune escape

Due to the resulting immune tolerance via the NKG2A receptor on the one hand and the lack of immune activation via the NKG2C receptor on the other hand, infected tumor cells were able to spread easily in the in vitro studies of the research group. When the scientists blocked the NKG2A receptor using monoclonal antibodies (monalizumab), the natural killer cells controlled the growth of the infected tumor cells efficiently.

The scientists at the Medical University of Vienna were able to elucidate the LMP-1/HLA-E/NKG2A signaling pathway as central to the development of EBV-positive Hodgkins or non-Hodgkins lymphoma. The Epstein-Barr virus can trigger lymphoma when certain molecule variants of the signaling pathway come together on virus and host side - AND there is a genetically determined deficit in the activating NKG2C receptor of the natural killer cells.

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* Vietzen H et al. Inhibitory NKG2A+ and absent activating NKG2C+ NK cell responses are
associated with the development of EBV+ lymphomas. Front Immunol. 2023 Jun 22;14:1183788.

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