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The Journal of Experimental Medicine Oct 2023Cytokines produced in association with tumors can impair antitumor immune responses by reducing the abundance of type 1 conventional dendritic cells (cDC1), but the...
Cytokines produced in association with tumors can impair antitumor immune responses by reducing the abundance of type 1 conventional dendritic cells (cDC1), but the mechanism remains unclear. Here, we show that tumor-derived IL-6 generally reduces cDC development but selectively impairs cDC1 development in both murine and human systems through the induction of C/EBPβ in the common dendritic cell progenitor (CDP). C/EBPβ and NFIL3 compete for binding to sites in the Zeb2 -165 kb enhancer and support or repress Zeb2 expression, respectively. At homeostasis, pre-cDC1 specification occurs upon Nfil3 induction and consequent Zeb2 suppression. However, IL-6 strongly induces C/EBPβ expression in CDPs. Importantly, the ability of IL-6 to impair cDC development is dependent on the presence of C/EBPβ binding sites in the Zeb2 -165 kb enhancer, as this effect is lost in Δ1+2+3 mutant mice in which these binding sites are mutated. These results explain how tumor-associated IL-6 suppresses cDC1 development and suggest therapeutic approaches preventing abnormal C/EBPβ induction in CDPs may help reestablish cDC1 development to enhance antitumor immunity.
Topics: Humans; Animals; Mice; Interleukin-6; Binding Sites; Cytokines; Dendritic Cells; Homeostasis
PubMed: 37432392
DOI: 10.1084/jem.20221757 -
Nature Biomedical Engineering May 2024Lipid nanoparticles (LNPs) can be designed to potentiate cancer immunotherapy by promoting their uptake by antigen-presenting cells, stimulating the maturation of these...
Lipid nanoparticles (LNPs) can be designed to potentiate cancer immunotherapy by promoting their uptake by antigen-presenting cells, stimulating the maturation of these cells and modulating the activity of adjuvants. Here we report an LNP-screening method for the optimization of the type of helper lipid and of lipid-component ratios to enhance the delivery of tumour-antigen-encoding mRNA to dendritic cells and their immune-activation profile towards enhanced antitumour activity. The method involves screening for LNPs that enhance the maturation of bone-marrow-derived dendritic cells and antigen presentation in vitro, followed by assessing immune activation and tumour-growth suppression in a mouse model of melanoma after subcutaneous or intramuscular delivery of the LNPs. We found that the most potent antitumour activity, especially when combined with immune checkpoint inhibitors, resulted from a coordinated attack by T cells and NK cells, triggered by LNPs that elicited strong immune activity in both type-1 and type-2 T helper cells. Our findings highlight the importance of optimizing the LNP composition of mRNA-based cancer vaccines to tailor antigen-specific immune-activation profiles.
Topics: Animals; Nanoparticles; Mice; Mice, Inbred C57BL; T-Lymphocytes, Helper-Inducer; Dendritic Cells; Lipids; Immunotherapy; Cancer Vaccines; Female; Melanoma, Experimental; Antigens, Neoplasm; RNA, Messenger; Liposomes
PubMed: 38082180
DOI: 10.1038/s41551-023-01131-0 -
Arthritis Research & Therapy Oct 2023Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by joint pain and swelling, synovial hyperplasia, cartilage damage, and bone destruction. The... (Review)
Review
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by joint pain and swelling, synovial hyperplasia, cartilage damage, and bone destruction. The mechanisms of dendritic cell (DC) and T cell-mediated crosstalk have gradually become a focus of attention. DCs regulate the proliferation and differentiation of CD4 T cell subtypes through different cytokines, surface molecules, and antigen presentation. DC-T cell crosstalk also blocks antigen presentation by DCs, ultimately maintaining immune tolerance. DC-T cell crosstalk mainly involves chemokines, surface molecules (TonEBP, NFATc1), the PD-L1/PD-1 signalling axis, and the TGF-β signalling axis. In addition, DC-T cell crosstalk in RA is affected by glycolysis, reactive oxygen species, vitamin D, and other factors. These factors lead to the formation of an extremely complex regulatory network involving various mechanisms. This article reviews the key immune targets of DC-T cell crosstalk and elucidates the mechanism of DC-T cell crosstalk in RA to provide a basis for the treatment of patients with RA.
Topics: Humans; T-Lymphocytes; Arthritis, Rheumatoid; Cytokines; Signal Transduction; Dendritic Cells
PubMed: 37798668
DOI: 10.1186/s13075-023-03159-8 -
Blood Advances Nov 2023Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy....
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.
Topics: Humans; Middle Aged; Transplantation, Homologous; Neoplasm Recurrence, Local; Hematopoietic Stem Cell Transplantation; Acute Disease; Myeloproliferative Disorders; Chronic Disease; Recurrence; Dendritic Cells
PubMed: 37792849
DOI: 10.1182/bloodadvances.2023011308 -
Advanced Science (Weinheim,... Jul 2023In situ vaccination can elicit systemic antitumor immunity to potentiate immune checkpoint blockade (ICB) in poorly immunogenic tumors. Herein, an immunogenic cell death...
In situ vaccination can elicit systemic antitumor immunity to potentiate immune checkpoint blockade (ICB) in poorly immunogenic tumors. Herein, an immunogenic cell death (ICD) inducer for in situ vaccination, which is based on a mitochondria-targeting modification of fenofibric acid (FFa), a lipid-lowering drug with potential inhibitory efficacy of respiratory complex I is developed. Mitochondria-targeting FFa (Mito-FFa) inhibits complex I efficiently and increases mitochondrial ROS (mtROS) generation, which further triggers endoplasmic reticulum (ER) stress with unprecedented calreticulin (CRT) exposure on tumor cellular membranes. Moreover, the generated mtROS also oxidizes mitochondrial DNA (mtDNA) and promotes it leakage into the cytoplasm for cGAS-STING-dependent type I interferon (IFN-I) secretion. The synchronous CRT exposure and IFN-I secretion successively improve the uptake of tumor antigens, maturation of dendritic cells (DCs) and cross-priming of CD8 T cells. In a poorly immunogenic 4T1 tumor model, a single intratumoral (i.t.) Mito-FFa injection turns immune-cold tumors into hot ones and elicits systemic tumor-specific CD8 T cells responses against primary and metastatic tumors. Furthermore, the synergistic effect with PD-L1 blockade and good bio-safety of i.t. Mito-FFa administration suggest the great translational potential of Mito-FFa in tumor immunotherapy.
Topics: Humans; CD8-Positive T-Lymphocytes; Dendritic Cells; Neoplasms; Immunotherapy; Mitochondria
PubMed: 37127892
DOI: 10.1002/advs.202300286 -
Emerging Microbes & Infections Dec 2023The persistent pandemic of coronavirus disease in 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently poses a major... (Review)
Review
The persistent pandemic of coronavirus disease in 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently poses a major infectious threat to public health around the world. COVID-19 is an infectious disease characterized by strong induction of inflammatory cytokines, progressive lung inflammation, and potential multiple organs dysfunction. SARS-CoV-2 infection is closely related to the innate immune system and adaptive immune system. Dendritic cells (DCs), as a "bridge" connecting innate immunity and adaptive immunity, play many important roles in viral diseases. In this review, we will pay special attention to the possible mechanism of dendritic cells in human viral transmission and clinical progression of diseases, as well as the reduction and dysfunction of DCs in severe SARS-CoV-2 infection, so as to understand the mechanism and immunological characteristics of SARS-CoV-2 infection.
Topics: Humans; COVID-19; SARS-CoV-2; Cytokines; Immunity, Innate; Dendritic Cells
PubMed: 36946172
DOI: 10.1080/22221751.2023.2195019 -
Frontiers in Immunology 2023Glioblastoma is an aggressive primary brain tumor that has seen few advances in treatments for over 20 years. In response to this desperate clinical need, multiple... (Review)
Review
Glioblastoma is an aggressive primary brain tumor that has seen few advances in treatments for over 20 years. In response to this desperate clinical need, multiple immunotherapy strategies are under development, including CAR-T cells, immune checkpoint inhibitors, oncolytic viruses and dendritic cell vaccines, although these approaches are yet to yield significant clinical benefit. Potential reasons for the lack of success so far include the immunosuppressive tumor microenvironment, the blood-brain barrier, and systemic changes to the immune system driven by both the tumor and its treatment. Furthermore, while T cells are essential effector cells for tumor control, dendritic cells play an equally important role in T cell activation, and emerging evidence suggests the dendritic cell compartment may be deeply compromised in glioblastoma patients. In this review, we describe the immunotherapy approaches currently under development for glioblastoma and the challenges faced, with a particular emphasis on the critical role of the dendritic cell-T cell axis. We suggest a number of strategies that could be used to boost dendritic cell number and function and propose that the use of these in combination with T cell-targeting strategies could lead to successful tumor control.
Topics: Humans; Glioblastoma; T-Lymphocytes; Immunotherapy; Oncolytic Viruses; Dendritic Cells; Tumor Microenvironment
PubMed: 37928547
DOI: 10.3389/fimmu.2023.1261257 -
Kidney International Sep 2023Ischemia reperfusion injury is a common precipitant of acute kidney injury that occurs following disrupted perfusion to the kidney. This includes blood loss and...
Ischemia reperfusion injury is a common precipitant of acute kidney injury that occurs following disrupted perfusion to the kidney. This includes blood loss and hemodynamic shock, as well as during retrieval for deceased donor kidney transplantation. Acute kidney injury is associated with adverse long-term clinical outcomes and requires effective interventions that can modify the disease process. Immunomodulatory cell therapies such as tolerogenic dendritic cells remain a promising tool, and here we tested the hypothesis that adoptively transferred tolerogenic dendritic cells can limit kidney injury. The phenotypic and genomic signatures of bone marrow-derived syngeneic or allogeneic, Vitamin-D3/IL-10-conditioned tolerogenic dendritic cells were assessed. These cells were characterized by high PD-L1:CD86, elevated IL-10, restricted IL-12p70 secretion and a suppressed transcriptomic inflammatory profile. When infused systemically, these cells successfully abrogated kidney injury without modifying infiltrating inflammatory cell populations. They also provided protection against ischemia reperfusion injury in mice pre-treated with liposomal clodronate, suggesting the process was regulated by live, rather than reprocessed cells. Co-culture experiments and spatial transcriptomic analysis confirmed reduced kidney tubular epithelial cell injury. Thus, our data provide strong evidence that peri-operatively administered tolerogenic dendritic cells have the ability to protect against acute kidney injury and warrants further exploration as a therapeutic option. This technology may provide a clinical advantage for bench-to-bedside translation to affect patient outcomes.
Topics: Mice; Animals; Interleukin-10; Acute Kidney Injury; Kidney; Dendritic Cells; Reperfusion Injury
PubMed: 37244471
DOI: 10.1016/j.kint.2023.05.008 -
Molecular Immunology Jul 2023Since their discovery, the identity of plasmacytoid dendritic cells (pDCs) has been at the center of a continuous dispute in the field, and their classification as... (Review)
Review
Since their discovery, the identity of plasmacytoid dendritic cells (pDCs) has been at the center of a continuous dispute in the field, and their classification as dendritic cells (DCs) has been recently re-challenged. pDCs are different enough from the rest of the DC family members to be considered a lineage of cells on their own. Unlike the exclusive myeloid ontogeny of cDCs, pDCs may have dual origin developing from myeloid and lymphoid progenitors. Moreover, pDCs have the unique ability to quickly secrete abundant levels of type I interferon (IFN-I) in response to viral infections. In addition, pDCs undergo a differentiation process after pathogen recognition that allows them to activate T cells, a feature that has been shown to be independent of presumed contaminating cells. Here, we aim to provide an overview of the historic and current understanding of pDCs and argue that their classification as either lymphoid or myeloid may be an oversimplification. Instead, we propose that the capacity of pDCs to link the innate and adaptive immune response by directly sensing pathogens and activating adaptive immune responses justify their inclusion within the DC network.
Topics: Adaptive Immunity; Cell Differentiation; Dendritic Cells; Immunity, Humoral; T-Lymphocytes
PubMed: 37269733
DOI: 10.1016/j.molimm.2023.05.007 -
International Journal of Molecular... Aug 2023Thrombocytes are numerous in the blood of aves (birds) and ichthyoids (fish). The origin of this cell type is a common hematopoietic stem cell giving rise to a cell that... (Review)
Review
Thrombocytes are numerous in the blood of aves (birds) and ichthyoids (fish). The origin of this cell type is a common hematopoietic stem cell giving rise to a cell that is active in blood coagulation, inflammatory functions, and the immune response in general. It has been well documented that thrombocytes can phagocytize small particles and bacteria. While phagocytosis with an associated oxidative burst has been reported for chicken thrombocytes, some questions remain as to the degradation capacity of phagosomes in ichthyoids. As innate cells, thrombocytes can be stimulated by bacterial, viral, and fungal pathogens to express altered gene expression. Furthermore, there have been observations that led researchers to state that platelets/thrombocytes are capable of serving as "professional antigen presenting cells" expressing CD40, CD80/86, MHC I, and MHC II. This indeed may be the case or, more likely at this time, provide supporting evidence that these cells aid and assist in the role of professional antigen-presenting cells to initiate adaptive immune responses.
Topics: Animals; Blood Platelets; Blood Coagulation; Antigen-Presenting Cells; B7-1 Antigen; Bacteriophages
PubMed: 37629130
DOI: 10.3390/ijms241612950