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

Ghita Ghislat (1) , Ammar Cheema (1) , Elodie Baudoin (1) , Christophe Verthuy (1) , Pedro Ballester (2) , Karine Crozat (3, 1) , Noudjoud Attaf (1) , Chuang Dong (1) , Pierre Milpied (1) , Bernard Malissen (1) , Nathalie Auphan-Anezin (1) , Thien Manh (1) , Marc Dalod (1) , Toby Lawrence (1, 4, 5, 6)

1 CIML - Centre d'Immunologie de Marseille - Luminy
2 CRCM - Centre de Recherche en Cancérologie de Marseille
3 MICMAC - Microenvironment, Cell Differentiation, Immunology and Cancer
4 King‘s College London
5 Xinxiang Medical University
6 Turing Center for Living Systems

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.

Domaines: Immunologie

Ghita Ghislat, Ammar Cheema, Elodie Baudoin, Christophe Verthuy, Pedro Ballester, et al.. NF-κB–dependent IRF1 activation programs cDC1 dendritic cells to drive antitumor immunity. Science Immunology, 2021, 6 (61), pp.eabg3570. ⟨10.1126/sciimmunol.abg3570⟩. ⟨hal-03329415⟩