Erra Diaz F,
Dalotto Moreno T,
Concomitant inhibition of PPARγ and mTORC1 induces the differentiation of human monocytes into highly immunogenic dendritic cells. Cell Rep. 2023;42(3):112156.
JGM, SS1, Humans, Monocytes, Granulocyte-Macrophage Colony-Stimulating Factor, PPAR gamma, Interleukin-4, Dendritic Cells, Cell Differentiation, Cells, Cultured
Cell Rep. 2023;42(3):112156.
This work was supported by grants from the Agencia Nacional de Promo- cio ́n Cient ́ıfica y Tecnolo ́gica, Argentina (PICT 2017-1616 and PICT 2018– 02844), and Universidad de Buenos Aires (UBA), Argentina (UBACyT 20020170100573BA) to J.G.
Monocytes can differentiate into macrophages (Mo-Macs) or dendritic cells (Mo-DCs). The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the differentiation of monocytes into Mo-Macs, while the combination of GM-CSF/interleukin (IL)-4 is widely used to generate Mo-DCs for clinical applications and to study human DC biology. Here, we report that pharmacological inhibition of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) in the presence of GM-CSF and the absence of IL-4 induces monocyte differentiation into Mo-DCs. Remarkably, we find that simultaneous inhibition of PPARγ and the nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) induces the differentiation of Mo-DCs with stronger phenotypic stability, superior immunogenicity, and a transcriptional profile characterized by a strong type I interferon (IFN) signature, a lower expression of a large set of tolerogenic genes, and the differential expression of several transcription factors compared with GM-CSF/IL-4 Mo-DCs. Our findings uncover a pathway that tailors Mo-DC differentiation with potential implications in the fields of DC vaccination and cancer immunotherapy.