Concomitant inhibition of PPARγ and mTORC1 induces the differentiation of human monocytes into highly immunogenic dendritic cells
Fernando Erra Diaz,
Ignacio Mazzitelli,
Lucía Bleichmar,
Claudia Melucci,
Asa Thibodeau,
Tomás Dalotto Moreno,
Radu Marches,
Gabriel A. Rabinovich,
Duygu Ucar,
Jorge Geffner
Affiliations
Fernando Erra Diaz
Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina
Ignacio Mazzitelli
Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina
Lucía Bleichmar
Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina
Claudia Melucci
Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina
Asa Thibodeau
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
Tomás Dalotto Moreno
Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
Radu Marches
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
Gabriel A. Rabinovich
Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina; Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Duygu Ucar
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06030, USA; Institute for Systems Genomics, University of Connecticut Health Center, Farmington, CT 06030, USA; Corresponding author
Jorge Geffner
Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina; Corresponding author
Summary: 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.
