Retinoic Acid reprograms pDCs to resist the inhibitory effect of multiple myeloma

Plasmacytoid dendritic cells (pDCs) are a rare subset of dendritic cells in the body, distinguished by their secretion of large amounts of IFN-a upon activation by pathogen-derived ligands. pDCs express high levels of TLR7 and TLR9 in endosomes, endoplasmic reticulum, and lysosomes, enabling them to recognize pathogen-derived RNA and DNA containing CpG sequences, as well as synthetic ligands. However, in patients with multiple myeloma, pDCs exhibit functional impairment, characterized by a loss of both IFN-a secretion capacity and their ability to perform pro-tumor functions. In our previous high-throughput drug screening study, we identified that all-trans retinoic acid (ATRA) may have the potential to enhance and restore the IFN-a secretion capacity of pDCs. Therefore, we investigated the changes in gene transcription levels in human primary pDCs treated with ATRA and CpG through RNA sequencing (RNA-seq). The RNA-seq analysis of pDCs revealed that following ATRA treatment, the expression of retinoic acid-induced gene 1 (RIG-I) and numerous related interferon-stimulated genes (ISGs) associated with the secondary response to type I interferon were significantly upregulated. Overall design: To investigate the mechanism by which ATRA enhances the secretion of IFNA by pDCs, we isolated pDCs from human peripheral blood and stimulated them with different compounds for 6 hours. ATRA group were treated with 10nM ATRA; CpG group were treated with 1mM CpG; CpG_ATRA group were treated with 10nM ATRA and 1mM CpG and the control group was grown in the same culture conditions without the addition of any drugs.