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 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.
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasße 52, 20246 Hamburg, Germany.
Thomas
T
Stübig
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasße 52, 20246 Hamburg, Germany.
Anita
0000-0002-9993-0886
A
Badbaran
Department of Oncology/Hematology, University Medical Center Hamburg-Eppendorf, Martinistrasße 52, 20246 Hamburg, Germany.
Tim
T
Luetkens
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasße 52, 20246 Hamburg, Germany.
York
Y
Hildebrandt
Department of Oncology/Hematology, University Medical Center Hamburg-Eppendorf, Martinistrasße 52, 20246 Hamburg, Germany.
Djordje
D
Atanackovic
Department for Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasße 52, 20246 Hamburg, Germany.
Thomas M C
TM
Binder
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasße 52, 20246 Hamburg, Germany.
Boris
B
Fehse
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasße 52, 20246 Hamburg, Germany.
Nicolaus
N
Kröger
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D019070:Cell Lineage; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation; D020014:K562 Cells; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D033581:Stem Cell Transplantation; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D018417:Th1 Cells / Q000166:cytology*; D014184:Transplantation, Homologous
D000964:Antimetabolites, Antineoplastic; D007770:L-Lactate Dehydrogenase; D001374:Azacitidine