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-α 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-α 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-α 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. 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.