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IL-6 selectively suppresses cDC1 specification via C/EBPβ.
Sunkyung Kim1, Jing Chen1, Suin Jo1
1Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
The Journal of Experimental Medicine
|July 11, 2023
Summary
Tumor-associated IL-6 impairs antitumor immunity by reducing type 1 conventional dendritic cells (cDC1). This occurs via C/EBPβ induction in dendritic cell progenitors, hindering cDC1 development and suggesting new therapeutic targets.
Area of Science:
- Immunology
- Cell Biology
- Cancer Research
Background:
- Tumor-derived cytokines can suppress anti-tumor immune responses.
- Reduced numbers of type 1 conventional dendritic cells (cDC1) are linked to impaired anti-tumor immunity, but the underlying mechanisms are not fully understood.
- Interleukin-6 (IL-6) is a cytokine often found in tumor microenvironments.
Purpose of the Study:
- To elucidate the mechanism by which tumor-associated IL-6 reduces cDC1 populations.
- To investigate the role of transcription factors C/EBPβ and NFIL3 in regulating cDC1 development under IL-6 influence.
- To identify potential therapeutic strategies to restore cDC1 function in cancer.
Main Methods:
- Utilized murine and human cell systems to study dendritic cell (DC) development.
- Investigated the role of transcription factors C/EBPβ and NFIL3 in regulating Zeb2 expression.
- Employed mutant mice (Δ1+2+3) lacking specific binding sites in the Zeb2 enhancer to assess IL-6 effects.
Main Results:
- Tumor-derived IL-6 reduces overall DC development but selectively impairs cDC1 development.
- IL-6 induces C/EBPβ in common dendritic cell progenitors (CDPs), which competes with NFIL3 for Zeb2 enhancer binding.
- Impairment of cDC1 development by IL-6 is dependent on C/EBPβ binding sites within the Zeb2 enhancer, as shown in mutant mice.
Conclusions:
- Tumor-associated IL-6 suppresses cDC1 development by inducing C/EBPβ in CDPs, disrupting the NFIL3-mediated regulation of Zeb2.
- This mechanism explains the reduction in cDC1s observed in tumor-bearing hosts.
- Targeting abnormal C/EBPβ induction in CDPs could be a viable strategy to enhance anti-tumor immunity by restoring cDC1 development.
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