| First Author | Ghislat G | Year | 2021 |
| Journal | Sci Immunol | Volume | 6 |
| Issue | 61 | PubMed ID | 34244313 |
| Mgi Jnum | J:345013 | Mgi Id | MGI:7444869 |
| Doi | 10.1126/sciimmunol.abg3570 | Citation | Ghislat G, et al. (2021) NF-kappaB-dependent IRF1 activation programs cDC1 dendritic cells to drive antitumor immunity. Sci Immunol 6(61):eabg3570 |
| abstractText | 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 kappaB (NF-kappaB) and interferon (IFN) pathways to be highly enriched in a subset of functionally mature cDC1s. We identified an NF-kappaB-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-kappaB and IFN signaling pathways. This maturation process was perturbed by specific inactivation of either NF-kappaB 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-kappaB/IRF1 axis in association with cDC1s is linked with improved clinical outcome. The NF-kappaB/IRF1 axis in cDC1s may therefore represent an important focal point for the development of new diagnostic and therapeutic approaches to improve cancer immunotherapy. |
