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.
Author Info: (1) CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. (2) CNRS, INSERM, Centre d'I
Author Info: (1) CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. (2) CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. (3) CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. (4) CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. (5) Cancer Research Center of Marseille CRCM, INSERM, Institut Paoli-Calmettes, Aix-Marseille University, CNRS, 13009 Marseille, France. (6) CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. (7) CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. (8) CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. (9) CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. (10) CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. (11) CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. (12) CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. (13) CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. (14) CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Turing Center for Living Systems, Aix-Marseille University, 13009 Marseille, France. toby.lawrence@kcl.ac.uk. Centre for Inflammation Biology and Cancer Immunology, Cancer Research UK King's Health Partners Centre, School of Immunology and Microbial Sciences, King's College London, London SE1 1UL, UK. Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.
