RRC ID 76635
Author Kim S, Chen J, Jo S, Ou F, Ferris ST, Liu TT, Ohara RA, Anderson DA, Wu R, Chen MY, Gillanders WE, Gillanders WE, Murphy TL, Murphy KM.
Title IL-6 selectively suppresses cDC1 specification via C/EBPβ.
Journal J Exp Med
Abstract Cytokines produced in association with tumors can impair antitumor immune responses by reducing the abundance of type 1 conventional dendritic cells (cDC1), but the mechanism remains unclear. Here, we show that tumor-derived IL-6 generally reduces cDC development but selectively impairs cDC1 development in both murine and human systems through the induction of C/EBPβ in the common dendritic cell progenitor (CDP). C/EBPβ and NFIL3 compete for binding to sites in the Zeb2 -165 kb enhancer and support or repress Zeb2 expression, respectively. At homeostasis, pre-cDC1 specification occurs upon Nfil3 induction and consequent Zeb2 suppression. However, IL-6 strongly induces C/EBPβ expression in CDPs. Importantly, the ability of IL-6 to impair cDC development is dependent on the presence of C/EBPβ binding sites in the Zeb2 -165 kb enhancer, as this effect is lost in Δ1+2+3 mutant mice in which these binding sites are mutated. These results explain how tumor-associated IL-6 suppresses cDC1 development and suggest therapeutic approaches preventing abnormal C/EBPβ induction in CDPs may help reestablish cDC1 development to enhance antitumor immunity.
Volume 220(10)
Published 2023-10-2
DOI 10.1084/jem.20221757
PII 214227
PMID 37432392
PMC PMC10336151
MeSH Animals Binding Sites Cytokines* Dendritic Cells Homeostasis Humans Interleukin-6* Mice
IF 11.743
Mice RBRC09240