GSE131792
Inhibition of Lysine-Specific Demethylase-1 in Myelodysplastic Syndrome Progenitors Restores Differentiation of CD141Hi Conventional Dendritic Cells
Immunotherapeutic approaches to treat patients with myelodysplastic syndromes (MDS) show promise but progress is hindered by our incomplete knowledge of the immunologic milieu. In a recent phase I trial, we found that vaccination of MDS patients against the tumor antigen NY-ESO-1 activated antigen-specific adaptive immune responses in patients with higher numbers of CD141Hi conventional dendritic cells (cDCs). In solid tumor models, the CD141Hi cDC is critical for initiating anti-tumor immune responses but its impact in myeloid malignancies is unknown. In a series of studies using human samples and mouse models, we tested the hypothesis that MDS patients would exhibit decreased quantity and quality of CD141Hi cDCs due to myeloid dysplasia. Overall, we found CD141Hi cDCs were decreased in MDS patients' bone marrow and that decreased numbers of CD141Hi cDCs were associated with reduced overall survival. MDS patients had reduced numbers of DC committed progenitors and their progenitors expressed lower levels of the transcription factor interferon regulatory factor-8 (IRF8), a master regulator of CD141Hi cDC differentiation. Induction of IRF8 expression in mouse, healthy human and MDS patient progenitors using an inhibitor of lysine-specific demethylase-1 (LSD1) increased CD141Hi cDC differentiation. These data reveal a previously unrecognized factor of the immune microenvironment in MDS and suggest intriguing connections between epigenetic regulation of CD141Hi cDC differentiation in MDS and the ability to translate these mechanisms to improve immunotherapy for MDS patients. Overall design: 32 samples; 18 NBM and 14 VP; 10 CD141Hi, 11 CD1c and 11 CD34 cell types.