IL-6 selectively suppresses cDC1 specification via C/EBP

We show that tumor-derived IL-6 blocks the development of type 1 classical dendritic cells through the induction of C/EBP & beta; in the common dendritic cell progenitor, which supports Zeb2 expression in the -165 kb enhancer, thereby preventing pre-cDC1 specification. 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/EBP & beta; in the common dendritic cell progenitor (CDP). C/EBP & beta; 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/EBP & beta; expression in CDPs. Importantly, the ability of IL-6 to impair cDC development is dependent on the presence of C/EBP & beta; binding sites in the Zeb2 -165 kb enhancer, as this effect is lost in & UDelta;1+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/EBP & beta; induction in CDPs may help reestablish cDC1 development to enhance antitumor immunity.