| First Author | Kim S | Year | 2023 |
| Journal | J Exp Med | Volume | 220 |
| Issue | 10 | PubMed ID | 37432392 |
| Mgi Jnum | J:343149 | Mgi Id | MGI:7564178 |
| Doi | 10.1084/jem.20221757 | Citation | Kim S, et al. (2023) IL-6 selectively suppresses cDC1 specification via C/EBPbeta. J Exp Med 220(10) |
| abstractText | 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/EBPbeta in the common dendritic cell progenitor (CDP). C/EBPbeta 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/EBPbeta expression in CDPs. Importantly, the ability of IL-6 to impair cDC development is dependent on the presence of C/EBPbeta binding sites in the Zeb2 -165 kb enhancer, as this effect is lost in Delta1+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/EBPbeta induction in CDPs may help reestablish cDC1 development to enhance antitumor immunity. |
