TY - JOUR
T1 - IL-6 selectively suppresses cDC1 specification via C/EBPβ
AU - Kim, Sunkyung
AU - Chen, Jing
AU - Jo, Suin
AU - Ou, Feiya
AU - Ferris, Stephen T.
AU - Liu, Tian Tian
AU - Ohara, Ray A.
AU - Anderson, David A.
AU - Wu, Renee
AU - Chen, Michael Y.
AU - Gillanders, William E.
AU - Gillanders, William E.
AU - Murphy, Theresa L.
AU - Murphy, Kenneth M.
N1 - Publisher Copyright:
© 2023 Kim et al.
PY - 2023/10/2
Y1 - 2023/10/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85164302026&partnerID=8YFLogxK
U2 - 10.1084/jem.20221757
DO - 10.1084/jem.20221757
M3 - Article
C2 - 37432392
AN - SCOPUS:85164302026
SN - 0022-1007
VL - 220
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
M1 - e20221757
ER -