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Transcriptional analysis of dendritic cells upon TLR stimulation reveals an immunosuppressive profile [PLF scRNA-seq]

ABSTRACT: Dendritic cells (DCs) simultaneously prime and dampen the immune response. The transcriptional program that regulates immunosuppression in DCs is currently unknown. Here we identified ETS homologous factor as a key transcription factor that regulates DC immunosuppression.

ORGANISM(S): Mus musculus

PROVIDER: GSE260859 | GEO | 2025/03/01

REPOSITORIES: GEO

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Project description:CD74 is a cell-surface receptor for the cytokine macrophage migration inhibitory factor (MIF). MIF binding to CD74 induces a signaling cascade resulting in the release of its cytosolic intracellular domain (CD74-ICD), which regulates transcription in naive B and chronic lymphocytic leukemia (CLL) cells. In the current study, we investigated the role of CD74 in the regulation of the immunosuppressive tumor microenvironment (TME) in triple-negative breast cancer (TNBC). TNBC is the most aggressive breast cancer subtype, in which there is a massive infiltration of immune cells to the tumor microenvironment, making this tumor a good candidate for immunotherapy. The tumor and immune cells in TNBC express high levels of CD74, however, the function of this receptor in this environment was not fully characterized. Regulatory B cells (Bregs) and tolerogenic dendritic cells )tol-DCs( were previously shown to attenuate the antitumor immune response in TNBC. Here, we demonstrate that CD74 enhances tumor growth by inducing the expansion of tumor-infiltrating tol-DCs and Bregs. Utilizing CD74-KO mice, conditionally CD74 -/- Cre-flox mice lacking CD74 in CD23+ mature B cells and mice lacking CD74 in the CD11c+ population and a CD74 inhibitor (DRQ), revealed that MIF secreted from the tumor cells activate CD74 expressed on DCs. This activation induces the binding of CD74-ICD to the SP1 promotor, resulting in the upregulation of SP1 expression. SP1 binds the IL-1β promotor, leading to the downregulation of its transcription. The reduced levels of IL-1β lead to decreased anti-tumor activity by allowing expansion of the tol-DC, which induce the expansion of the Breg population, suggesting the cross-talk between these two populations. Taken together, these results suggest that CD74+ CD11c+ DCs are the dominant cell type involved in the regulation of the TNBC progression. These findings indicate that CD74 might serve as a novel therapeutic target in triple-negative breast cancer.

Project description:Abstract Two major dendritic cell (DC) subsets have been described in the islets of mice: The immunogenic CD8Î±-CD11b+ DCs and the tolerogenic CD8Î±+CD103+ DCs. We have recently reported on reduced numbers of the minor population of tolerogenic CD8Î±+CD103+ DCs in the pancreas of 5 week old pre-diabetic non-obese diabetic (NOD) mice. Aim: To analyze also the larger subset of CD11c+CD8Î±- DCs isolated from the pancreas of pre-diabetic NOD mice 1) for maturation and tolerance inducing molecules found abnormally expressed on CD8Î±+CD103+ DCs, and 2) for genome-wide gene expression to further elucidate abnormalities in underlying gene expression networks. Methods: CD11c+CD8Î±- DCs were isolated from 5 week old C57BL/6 and NOD pancreas. Expression of cell surface markers including CD86, CCR5, CD11b, CD103, Clec9a, CD24 and CD200R3 were measured by FACS. Genome-wide gene expression by microarray was assessed during the steady state and after in vitro LPS stimulation. Results: The steady state pancreatic CD11c+ CD8Î±- DCs during the pre-diabetic stage showed: 1) A reduced expression of several gene networks important for the prime functions of the cell, such as for cell renewal, immune stimulation and immune tolerance induction, for migration and for the provision of growth factors for beta cell regeneration. This general deficiency state was corroborated by a reduced in vivo proliferation (BrdU incorporation) of the cells and the reduced expression in FACS analysis of CD86, CCR5, CD103, Clec9a, CD24 and CD200R3 on the cells. 2) A hyper reactivity of these cells to LPS correlated with an enhanced pro-inflammatory state characterized by altered expression of a number of classical pro-inflammatory factors and cytokines. Conclusion: The NOD CD11c+CD8Î±- DCs seem to be Janus-faced depending on the conditions: Deficient in steady state with reduced immune stimulation capabilities also for tolerance induction; over-inflammatory with a molecular profile suggesting a preferential stimulatory capacity for Th1 cells when encountering a Pathogen-Associated Molecular Pattern (PAMP) in the form of LPS. We used microarray gene expression analysis to explain the abnormal expression of several cell surface markers involved in tolerace, migration and maturation in the steady-state and to measure the effect of a PAMP such as LPS We isolated RNA from FACS sorted CD11c+CD8Î±- DCs in 10 pooled pancreases from pre-diabetic NOD and non-diabetic C57BL/6 mice at 5 weeks. In addition, we treated in another experiment the isolated pancreas DCs with LPS (and PBS), incubated for 18h and measured gene expression. We compared gene expression between strains NOD vs C57BL/6 under steady-state and after in-vitro LPS/PBS stimulation.

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Transcriptional analysis of dendritic cells upon TLR stimulation reveals an immunosuppressive profile [PLF scRNA-seq]

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