Hilmenyuk, Tamara; Ruckstuhl, Carla A.; Hayoz, Michael; Berchtold, Christian; Nuoffer, Jean-Marc; Solanki, Shyam; Keun, Hector C.; Beavis, Paul A.; Riether, Carsten; Ochsenbein, Adrian F. (2018). T cell inhibitory mechanisms in a model of aggressive Non-Hodgkin's Lymphoma. Oncoimmunology, 7(1), e1365997. Landes Bioscience 10.1080/2162402x.2017.1365997
Full text not available from this repository.A reduced immune surveillance due to immune deficiency or treatment with immunosuppressive drugs is associated with a higher risk to develop aggressive Non-Hodgkin's lymphoma (NHL). Nevertheless, NHL also develops in immunocompetent patients indicating an escape from the immune system. T cell function in advanced aggressive lymphoma is not well characterized and the molecular mechanisms how malignant B cells influence T cell function are ill-defined. We therefore studied T cell function in Eμ-myc transgenic mice that develop an aggressive B cell lymphoma with some similarities to human Burkitt-lymphoma (BL). In advanced lymphoma, the number of T cells was severely reduced and the remaining CD4+ and CD8+ T cells lost the capacity to produce effector cytokines and expand upon re-stimulation. T cells in lymphoma-bearing mice were characterized by the expression of the immune inhibitory molecules programmed death (PD)-1, 2B4 and lymphocyte activation protein (LAG)-3. The proto-oncogene c-Myc not only drives cell proliferation and disease progression but also induces apoptosis of the malignant cells. We found that apoptotic lymphoma cells release purine metabolites that inhibit T cell function. Taken together, our data document that the characteristic high cell turnover and apoptotic rate in aggressive NHL induce a severe T cell dysfunction mediated by several immune-inhibitory mechanisms including ligation of inhibitory ligands and purine metabolites. Blocking a single mechanism only partially restored T cell function and did not increase survival of lymphoma mice.
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