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

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 kappa B (NF-kappa B) and interferon (IFN) pathways to be highly enriched in a subset of functionally mature cDC1s. We identified an NF-kappa B-dependent and IFN-gamma-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-kappa B and IFN signaling pathways. This maturation process was perturbed by specific inactivation of either NF-kappa B or IFN regulatory factor 1 (IRF1) in cDC1s, resulting in impaired expression of IFN-gamma-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-kappa B/IRF1 axis in association with cDC1s is linked with improved clinical outcome. The NF-kappa B/IRF1 axis in cDC1s may therefore represent an important focal point for the development of new diagnostic and therapeutic approaches to improve cancer immunotherapy.

Automated summary

Through single-cell transcriptomics, it was discovered that nuclear factor kappa B (NF-kappa B) and interferon (IFN) pathways are highly enriched in a subset of functionally mature conventional type 1 dendritic cells (cDC1s). The dynamic reprogramming of tumor-infiltrating cDC1s by NF-kappa B and IFN signaling pathways affects the recruitment and activation of antitumoral CD8(+) T cells. Activation of the NF-kappa B/IRF1 axis in cDC1s is associated with improved clinical outcomes for patients with melanoma, suggesting it may be a key focal point for new diagnostic and therapeutic approaches in cancer immunotherapy.