5-Azacytidine Promotes an Inhibitory T-Cell Phenotype and Impairs Immune Mediated Antileukemic Activity

Demethylating agent, 5-Azacytidine (5-Aza), has been shown to be active in treatment of myeloid malignancies. 5-Aza enhances anticancer immunity, by increasing expression of tumor-associated antigens. However, the impact of 5-Aza immune responses remains poorly understood. Here, T-cell mediated tumo...

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Published in:Mediators of Inflammation 2014-01, Vol.2014 (4), p.172-183
Main Authors: Kröger, Nicolaus, Binder, Thomas M. C., Atanackovic, Djordje, Hildebrandt, York, Luetkens, Tim, Badbaran, Anita, Stübig, Thomas, Fehse, Boris
Format: Article
Language:English
Subjects:
Antimetabolites, Antineoplastic - pharmacology
Azacitidine - pharmacology
CD8-Positive T-Lymphocytes - cytology
Cell Lineage
Disease susceptibility
Gene expression
Genetic aspects
HL-60 Cells
Humans
Inflammation
K562 Cells
L-Lactate Dehydrogenase - metabolism
Leukemia - drug therapy
Male
Middle Aged
Phenotype
Stem Cell Transplantation
T cells
T-Lymphocytes, Regulatory - cytology
Th1 Cells - cytology
Transplantation, Homologous
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Summary:Demethylating agent, 5-Azacytidine (5-Aza), has been shown to be active in treatment of myeloid malignancies. 5-Aza enhances anticancer immunity, by increasing expression of tumor-associated antigens. However, the impact of 5-Aza immune responses remains poorly understood. Here, T-cell mediated tumor immunity effects of 5-Aza, are investigated in vitro and in vivo. T-cells from healthy donors were treated with 5-Aza and analyzed by qRT-PCR and flow cytometry for changes in gene expression and phenotype. Functionality was assessed by a tumor lysis assay. Peripheral blood from patients treated with 5-Aza after alloSCT was monitored for changes in T-cell subpopulations. 5-Aza treatment resulted in a decrease in CD8+ T-cells, whereas CD4+ T-cells increased. Furthermore, numbers of IFN-γ+ T-helper 1 cells (Th1) were reduced, while Treg-cells showed substantial increase. Additionally, CD8+ T-cells exhibited limited killing capacity against leukemic target cells. In vivo data confirm the increase of Treg compartment, while CD8+ T-effector cell numbers were reduced. 5-Aza treatment results in a shift from cytotoxic to regulatory T-cells with a functional phenotype and a major reduction in proinflammatory Th1-cells, indicating a strong inhibition of tumor-specific T-cell immunity by 5-Aza.
ISSN:0962-9351
1466-1861
DOI:10.1155/2014/418292