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.
IL-6 selectively suppresses cDC1 specification via C/EBPβ
Disclosures: The authors declare no competing interests exist.
- Award Id(s): R01AI150297,R01CA248919,R21AI164142,R01AI162643,R21AI163421,T32CA009621
Sunkyung Kim, Jing Chen, Suin Jo, Feiya Ou, Stephen T. Ferris, Tian-Tian Liu, Ray A. Ohara, David A. Anderson, Renee Wu, Michael Y. Chen, William E. Gillanders, William E. Gillanders, Theresa L. Murphy, Kenneth M. Murphy; IL-6 selectively suppresses cDC1 specification via C/EBPβ. J Exp Med 2 October 2023; 220 (10): e20221757. doi: https://doi.org/10.1084/jem.20221757
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