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

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Science Immunology  09 Jul 2021:
Vol. 6, Issue 61, eabg3570
DOI: 10.1126/sciimmunol.abg3570

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Unleashing tumor cDC1

Conventional type 1 dendritic cells (cDC1s) perform specialized roles in antitumor immunity by processing and presenting tumor antigens that prime tumor-specific T cell responses. Using a mouse model of immunogenic tumor growth and single-cell transcriptomics, Ghislat et al. demonstrate that cDC1s require NF-κB signaling for their intratumoral maturation into antitumoral cDC1s capable of recruiting and activating tumor-specific T cells. IKKβ controlled the expression of IRF1, a transcription factor regulating interferon-mediated gene expression, and loss of either factor in cDC1 impaired their maturation and antitumoral immunity. These results highlight key molecular pathways involved in the development of full-fledged cDC1 capable of stimulating antitumoral T cell responses and suggest potential therapeutic targets for improving intratumoral DC function.


Conventional type 1 dendritic cells (cDC1s) are critical for antitumor immunity. They acquire antigens from dying tumor cells and cross-present them to CD8+ T cells, promoting the expansion of tumor-specific cytotoxic T cells. However, the signaling pathways that govern the antitumor functions of cDC1s in immunogenic tumors are poorly understood. Using single-cell transcriptomics to examine the molecular pathways regulating intratumoral cDC1 maturation, we found nuclear factor κB (NF-κB) and interferon (IFN) pathways to be highly enriched in a subset of functionally mature cDC1s. We identified an NF-κB–dependent and IFN-γ–regulated gene network in cDC1s, including cytokines and chemokines specialized in the recruitment and activation of cytotoxic T cells. By mapping the trajectory of intratumoral cDC1 maturation, we demonstrated the dynamic reprogramming of tumor-infiltrating cDC1s by NF-κB and IFN signaling pathways. This maturation process was perturbed by specific inactivation of either NF-κB or IFN regulatory factor 1 (IRF1) in cDC1s, resulting in impaired expression of IFN-γ–responsive genes and consequently a failure to efficiently recruit and activate antitumoral CD8+ T cells. Last, we demonstrate the relevance of these findings to patients with melanoma, showing that activation of the NF-κB/IRF1 axis in association with cDC1s is linked with improved clinical outcome. The NF-κB/IRF1 axis in cDC1s may therefore represent an important focal point for the development of new diagnostic and therapeutic approaches to improve cancer immunotherapy.

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