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An NF-κB/IRF1 axis programs cDC1 to drive antitumor immunity

ABSTRACT: Conventional type 1 dendritic cells (cDC1s) are critical for anti-tumor 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 anti -tumor functions of cDC1s are poorly understood. We mapped the molecular pathways regulating intratumoral cDC1 maturation using single cell RNA sequencing. We identified NF κB and IFN pathways as being highly enriched in a subset of functionally mature cDC1s. The specific targeting of NF-κB or IFN pathways in cDC1s prevented the recruitment and activation of CD8+ T cells and the control of tumor growth. We identified an NF-κB-dependent IFN-γ-regulated gene network in cDC1s, including cytokines and chemokines specialized in the recruitment and activation of cytotoxic T cells. We used single cell transcriptomes to map the trajectory of intra-tumoral cDC1 maturation which revealed 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 IRF1 in cDC1s, resulting in impaired expression of IFN-γ-responsive genes and consequently a failure to efficiently recruit and activate anti-tumoral CD8+ T cells. Finally, we demonstrate the relevance of these findings to cancer patients, 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 new diagnostic and therapeutic approaches to improve cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE171870 | GEO | 2021/08/16

REPOSITORIES: GEO

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An NF-κB/IRF1 axis programs cDC1 to drive antitumor immunity II

Project description:functions of cDC1s are poorly understood. We mapped the molecular pathways regulating intratumoral cDC1 maturation using single cell RNA sequencing. We identified NF-κB and IFN pathways as being highly enriched in a subset of functionally mature cDC1s. The specific targeting of NF-κB or IFN pathways in cDC1s prevented the recruitment and activation of CD8+ T cells and the control of tumor growth. We identified an NF-κB-dependent IFN-γ-regulated gene network in cDC1s, including cytokines and chemokines specialized in the recruitment and activation of cytotoxic T cells. We used single cell transcriptomes to map the trajectory of intra-tumoral cDC1 maturation which revealed 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 IRF1 in cDC1s, resulting in impaired expression of IFN-γ-responsive genes and consequently a failure to efficiently recruit and activate anti-tumoral CD8+ T cells. Finally, we demonstrate the relevance of these findings to cancer patients, 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 new diagnostic and therapeutic approaches to improve cancer immunotherapy.

2021-08-16 | GSE174089 | GEO

STAT3 Inhibits Autocrine Interferon Signaling in Type I Conventional Dendritic Cells

Project description:Type I conventional dendritic cells (cDC1s) are an essential antigen-presenting population, required for generating adaptive immunity against intracellular pathogens and tumors. While the transcriptional control of cDC1 development is well understood, the mechanisms by which extracellular stimuli affect cDC1 function remain unclear. Recently, we demonstrated that the cytokine IL-10 inhibits cDC1 maturation induced upon polyinosinic-polycytidylic acid (poly I:C) exposure via a STAT3-dependent mechanism. Furthermore, utilizing a tumor vaccine strategy, we found STAT3 restrains cDC1-mediated anti-tumor immunity. To understand the pathways by which IL-10 and STAT3 regulate cDC1s, we evaluated transcriptional responses by RNA-sequencing. Bioinformatic analyses indicated that many inflammatory pathways were enriched in cDC1s following poly I:C treatment, while interferon (IFN) signaling was uniquely inhibited by STAT3 upon concomitant exposure to IL-10. We found that poly I:C stimulated production of IFN-b and IFN-g from cDC1s. Concurrent exposure to IL-10 suppressed IFN-b and IFN-g secretion as well as accrual of phosphorylated STAT1 and expression of the IFN-response gene Cxcl10 in cDC1s. By contrast, Stat3-deficient cDC1s were refractory to IL-10, indicating STAT3 controls poly I:C-mediated IFN production and IFN transcriptional responses in cDC1s. Moreover, we found that maturation of cDC1s in response to poly I:C is dependent on the type I IFN receptor. Taken together, our data indicate STAT3 is essential for restraining autocrine type I IFN signaling in cDC1s elicited by poly I:C stimulation.

2022-07-26 | GSE188995 | GEO

ISR8 / IRF1-AS1 is relevant for IFNα and NF-κB responses

Project description:The study of the interferon (IFN) α-induced cell transcriptome has shown altered expression of several long non-coding RNAs (lncRNAs). ISR8 / IRF1-AS1 (IFN stimulated RNA 8), located close to IFN regulatory factor 1 (IRF1) coding gene, transcribes a lncRNA induced at early times after IFNα treatment or IRF1 or NF-κB activation. Depletion or overexpression of ISR8 RNA does not lead to detected deregulation of the IFN response. Surprisingly, disruption of ISR8 locus with CRISPR-Cas9 genome editing results in cells that fail to induce several key ISGs and pro-inflammatory cytokines after a trigger with IFNα or overexpression of IRF1 or the NF-κB subunit RELA. This suggests that the ISR8 locus may play a relevant role in IFNα and NF-κB pathways. Interestingly, IFNα, IRFs and NF-κB-responding luciferase reporters are normally induced in ISR8-disrupted cells when expressed from a plasmid but not when integrated into the genome. Therefore, IFNα and NF-κB pathways are functional to induce the expression of exogenous episomic transcripts but fail to activate transcription from genomic promoters. Transcription from these promoters is not restored with silencing inhibitors, by decreasing the levels of several negative regulators or by overexpression of inducers. Transcriptome analyses indicate that ISR8-disrupted cells have a drastic increase in the levels of negative regulators such as XIST and Zinc finger proteins. Our results agree with ISR8 loci being an enhancer region that is fundamental for proper antiviral and proinflammatory responses. These results are relevant because several SNPs located in the ISR8 region are associated with chronic inflammatory and autoimmune diseases including Crohn’s disease, inflammatory bowel disease, ulcerative colitis or asthma.

2022-06-03 | GSE205276 | GEO

Stromal remodeling regulates dendritic cell abundance and activity in the tumor microenvironment

Project description:Stimulatory type 1 conventional dendritic cells (cDC1s) engage in productive interactions with CD8+ effectors along tumor-stroma boundaries. The paradoxical accumulation of “poised” cDC1s within stromal sheets is unlikely to simply reflect passive exclusion from tumor cores. Drawing parallels with embryonic morphogenesis, we hypothesized that invasive margin stromal remodeling generates developmentally conserved cell fate cues that regulate cDC1 behavior. We find that, in human T cell-inflamed tumors, CD8+ T cells penetrate tumor nests, whereas cDC1s are confined within adjacent stroma that recurrently displays site-specific proteolysis of the matrix proteoglycan versican (VCAN), an essential organ-sculpting modification in development. VCAN is necessary, and its proteolytic fragment (matrikine) versikine is sufficient for cDC1 accumulation. Versikine does not influence tumor-seeding pre-DC differentiation; rather, it orchestrates a distinctive cDC1 activation program conferring exquisite sensitivity to DNA sensing, supported by atypical innate lymphoid cells. Thus, peritumoral stroma mimicking embryonic provisional matrix remodeling regulates cDC1 abundance and activity to elicit T cell-inflamed tumor microenvironments.

2022-05-16 | GSE199938 | GEO

An NF-κB/IRF1 axis programs cDC1 to drive antitumor immunity

Project description:An NF-κB/IRF1 axis programs cDC1 to drive antitumor immunity

| PRJNA721231 | ENA

An NF-κB/IRF1 axis programs cDC1 to drive antitumor immunity II

Project description:An NF-κB/IRF1 axis programs cDC1 to drive antitumor immunity II

| PRJNA728126 | ENA

Single-cell transcriptional profiling informs efficient reprogramming of human somatic cells to cross-presenting dendritic cells

Project description:Type-1 conventional dendritic cells (cDC1s) are rare immune cells critical for the induction of antigen-specific cytotoxic CD8+ T-cells. The genetic program driving human cDC1 specification remains largely unexplored. We have previously identified PU.1, IRF8 and BATF3 transcription factors as sufficient to induce cDC1 fate in mouse fibroblasts but reprogramming of human somatic cells was limited by low efficiencies. Here, we investigated single-cell transcriptional dynamics during human cDC1 reprogramming. Human induced cDC1s (hiDCs) generated from embryonic fibroblasts gradually acquire a global cDC1 transcriptional profile and activate antigen presentation signatures. Importantly, other DC subsets are not induced at the single-cell level. We extracted gene modules associated with successful reprogramming and identified inflammatory signaling and the cDC1-inducing transcription factor network as key drivers of the process. Combining IFN-γ, IFN-β and TNF-α with constitutive expression of cDC1-inducing transcription factors lead to improvement of reprogramming efficiency by 190-fold. hiDCs uptake dead cells, secrete inflammatory cytokines and perform antigen cross-presentation, a key cDC1 function. This approach allowed efficient hiDC1 generation from adult fibroblasts and mesenchymal stromal cells. Mechanistically, PU.1 shows dominant and independent chromatin targeting at early phases of reprogramming, recruiting IRF8 and BATF3 to shared binding sites. The cooperative binding at open enhancers and promoters leads to silencing of fibroblast genes and activation of a cDC1 program. These findings provide mechanistic insights into human cDC1 specification and reprogramming and represent a platform for generating patient-tailored cDC1s, a long-sought DC subset for vaccination strategies in cancer immunotherapy.

2022-03-05 | GSE162650 | GEO

Late stages of T-cell maturation in the thymus involve NF-κB and tonic type I interferon signaling

Project description:Positive selection occurs in the thymic cortex, but critical maturation events occur later in the medulla. We defined the precise stage at which T cells acquire competence to proliferate and emigrate. Transcriptome analysis of late gene changes suggested roles for NF-κB and interferon signaling. Mice lacking the IKK kinase TAK1, showed normal positive selection, but a specific block in functional maturation. NF-κB signaling provided protection from TNF, and was required for proliferation and emigration. Alternatively, the interferon signature was independent of NF-κB, and IFNαR deficient thymocytes showed reduced STAT1 levels and phenotypic abnormality, but were competent to proliferate. Thus, both NF-κB and tonic IFN signals are involved in the final maturation of thymocytes into naïve T cells.

2016-04-03 | GSE74078 | GEO

Cis-regulation between Irf8 enhancers during cDC1 development (CUT&RUN)

Project description:Type 1 classical dendritic cells (cDC1s) development requires the transcription factor IRF8, and IRF8 mutations cause severe combined immunodeficiency, including disseminated bacille Calmette-Guérin (BCG) disease. IRF8 regulated enhancers are required for Irf8 expression in early DC progenitors and mature cDC1s. The E-protein-dependent +41 kb enhancer gains accessibility and activates transcription in common DC progenitors (CDPs), and its depletion abrogated pre-cDC1s specification. The Batf3-dependent +32 kb enhancer gains accessibility and activates transcription in pre-cDC1 progenitors, and its depletion impaired cDC1 maturation. The +32 kb Irf8 enhancer locus bears an enhancer transcript, and the production of enhancer RNA (eRNA) Gm39266 is dependent on +41 kb Irf8 enhancer. It was unclear whether the +32 kb and +41 kb enhancers act independently or cooperate to regulate Irf8 expression. We dissected the mechanisms using +32/+41 compound heterozygous mice, and found that while the +41 kb enhancer suffices for pre-cDC1 progenitor specification, the +32 kb and +41 kb enhancers must reside on one allele to support cDC1 maturation. The +41 kb enhancer cis-regulates chromatin accessibility and BATF3 binding at +32 kb enhancer, independent of eRNA Gm39266 transcripts or transcription across +32 kb Irf8 enhancer.

2023-03-15 | GSE218991 | GEO

Cis-regulation between Irf8 enhancers during cDC1 development (ATAC-Seq)

2023-03-15 | GSE218990 | GEO

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