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

Abstract EN

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.