Activation of the autoimmunity checkpoint in B-cell neoplasms with viral oncogenes. Implication for therapeutic use in the future?

• Applicant: Dr. Anna Hecht de Gutierrez
• Subject Area: Hematology, Oncology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 316376607

The B-cell receptor (BCR) provides important survival signals in healthy as well as in malignant B-lymphocytes. During the normal course of B-cell development B-cells with intermediate BCR-activation are positively selected. Cells with activity below a minimum threshold are eliminated as well as autoreactive B-cells with hyperactive BCR. The classical therapeutic option in B-cell lymphomas is using the first mechanism: Inhibition of signaling molecules leads to low BCR signaling and cell death. However, B-cell lymphomas vary in their strength of BCR-activation and therefore in their sensibility to inhibition therapy. Moreover, resistance development is a frequent problem. A new innovative therapeutic strategy is using the second mechanism. Recently it was shown, that malignant B-cells which mimic a chronic active BCR-signal through an oncogene, are addicted to inhibitory signals to maintain an intermediate BCR-activation level. When these inhibitory signals are blocked, the cell is hyperactivated and undergoes cell death. This principle is called activation of the autoimmunity checkpoint (AIC). A range of agents has already been developed for the therapeutic use of this mechanism. But first it has to be investigated which types of lymphoma would respond to these therapies. One group of lymphomas is associated with viral infections. The viruses bring genes into the B-cell which mimic an active BCR.This research project studies the hypothesis that lymphomas with viral oncogenes that mimic BCR-activity are especially susceptible for the activation of the AIC. Agents which could be therapeutically used will be tested in vitro in cell lines and in vivo in mouse models. This could provide the foundation for the development of new therapeutic strategies for patients with virus-associated lymphomas.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Markus Müschen