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

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

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

UniBE Contributor:

Nuoffer, Jean-Marc; Riether, Carsten and Ochsenbein, Adrian

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2162-4011

Publisher:

Landes Bioscience

Language:

English

Submitter:

Jean-Marc Nuoffer

Date Deposited:

16 Apr 2018 15:14

Last Modified:

22 Apr 2018 02:20

Publisher DOI:

10.1080/2162402x.2017.1365997

PubMed ID:

29296517

URI:

https://boris.unibe.ch/id/eprint/110096

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