T cell inhibitory mechanisms in a model of aggressive Non-Hodgkin's Lymphoma
| Autor: | Hector C. Keun, Paul A. Beavis, Michael Hayoz, Carsten Riether, Christian Berchtold, Jean-Marc Nuoffer, Shyam Solanki, Tamara Hilmenyuk, Carla Alicia Ruckstuhl, Adrian F. Ochsenbein |
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| Rok vydání: | 2017 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
0301 basic medicine T cell Immunology T lymphocytes EXTRACELLULAR ATP Aggressive lymphoma URIC-ACID lcsh:RC254-282 HEMATOLOGIC MALIGNANCIES TOLERANCE INDUCTION 03 medical and health sciences LUNG-CANCER Immune system immune system diseases checkpoint inhibition hemic and lymphatic diseases C-MYC medicine Immunology and Allergy B-cell lymphoma Original Research TRANSGENIC MICE Science & Technology aggressive b cell nhl apoptosis t lymphocytes purine metabolites Cell growth Chemistry lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease PD-1 BLOCKADE Non-Hodgkin's lymphoma Lymphoma 030104 developmental biology medicine.anatomical_structure Aggressive B cell NHL Oncology ANTITUMOR IMMUNE-RESPONSES Cancer research CANCER-IMMUNOTHERAPY lcsh:RC581-607 Life Sciences & Biomedicine CD8 |
| Zdroj: | OncoImmunology, Vol 7, Iss 1 (2018) |
| ISSN: | 2162-4011 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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