Ghislat et al. investigated the molecular pathways regulating the antitumor functions of tumor-infiltrating cDC1s, and showed that cell-intrinsic NF-κB and IFN signaling pathways regulate intratumoral cDC1 maturation, CD8+ T cell recruitment and activation, and control of immunogenic tumors. NF-κB–mediated IFN regulatory factor 1 (IRF1) expression in cDC1s was required, and inactivation of either NF-κB or IRF1 in cDC1s abolished the recruitment and activation of CD8+ T cells. High expression of both the activated CD8+ T cell signature and the NF-κB/IRF1-dependent cytokine signature correlated with good prognosis in melanoma patients.
Contributed by Shishir Pant
ABSTRACT: 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.