T cell inhibitory mechanisms in a model of aggressive Non-Hodgkin's Lymphoma

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Title: T cell inhibitory mechanisms in a model of aggressive Non-Hodgkin's Lymphoma
Authors: Hilmenyuk, T
Ruckstuhl, CA
Hayoz, M
Berchtold, C
Nuoffer, J-M
Solanki, S
Keun, HC
Beavis, PA
Riether, C
Ochsenbein, AF
Item Type: Journal Article
Abstract: 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.
Issue Date: 21-Sep-2017
Date of Acceptance: 5-Aug-2017
URI: http://hdl.handle.net/10044/1/57309
DOI: https://dx.doi.org/10.1080/2162402X.2017.1365997
ISSN: 2162-4011
Publisher: Taylor & Francis
Journal / Book Title: OncoImmunology
Volume: 7
Issue: 1
Copyright Statement: © 2018 Taylor & Francis Group, LLC. This is an Accepted Manuscript of an article published by Taylor & Francis in OncoImmunology on 21 Sep 2017, available online: https://dx.doi.org/10.1080/2162402X.2017.1365997
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
Immunology
Aggressive B cell NHL
apoptosis
T lymphocytes
checkpoint inhibition
purine metabolites
ANTITUMOR IMMUNE-RESPONSES
C-MYC
TRANSGENIC MICE
HEMATOLOGIC MALIGNANCIES
CANCER-IMMUNOTHERAPY
TOLERANCE INDUCTION
EXTRACELLULAR ATP
PD-1 BLOCKADE
LUNG-CANCER
URIC-ACID
Publication Status: Published
Article Number: ARTN e1365997
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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