NF-κB-dependent IRF1 activation programs cDC1 dendritic cells to drive antitumor immunity

Area of Science:

• Immunology
• Cancer Biology
• Cell Signaling

Background:

• Conventional type 1 dendritic cells (cDC1s) are vital for initiating antitumor immune responses by cross-presenting tumor antigens to CD8+ T cells.
• The specific signaling pathways governing cDC1 maturation and function within the tumor microenvironment remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular pathways regulating the maturation and antitumor functions of intratumoral cDC1s.
• To investigate the role of nuclear factor κB (NF-κB) and interferon (IFN) signaling in cDC1-mediated anti-tumor immunity.

Main Methods:

• Single-cell transcriptomics was employed to analyze gene expression and map the maturation trajectory of intratumoral cDC1s.
• Functional studies involved the genetic inactivation of NF-κB and IFN regulatory factor 1 (IRF1) in cDC1s to assess their impact on T cell responses.

Main Results:

• NF-κB and IFN pathways were found to be highly enriched in functionally mature cDC1s.
• An NF-κB-dependent and IFN-γ-regulated gene network was identified in cDC1s, crucial for recruiting and activating cytotoxic T cells.
• Inactivation of NF-κB or IRF1 in cDC1s impaired anti-tumor CD8+ T cell responses.
• Activation of the NF-κB/IRF1 axis in cDC1s correlated with improved clinical outcomes in melanoma patients.

Conclusions:

• The NF-κB/IRF1 signaling axis dynamically regulates cDC1 maturation and antitumor functions.
• This axis is critical for effective recruitment and activation of CD8+ T cells against tumors.
• The NF-κB/IRF1 axis in cDC1s represents a potential therapeutic target for enhancing cancer immunotherapy.