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Nature Dec 2023People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. ), whose mechanism remains unknown....
People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. ), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in infected diabetics.
Topics: Animals; Mice; Acetyl Coenzyme A; Acetylation; Chromatin; Dendritic Cells; Diabetes Complications; Diabetes Mellitus; Disease Susceptibility; Glucose; Histones; Hyperglycemia; Lung; T-Lymphocytes; Virus Diseases; Viruses; Disease Models, Animal; Humans
PubMed: 38093014
DOI: 10.1038/s41586-023-06803-0 -
Cancer Discovery Nov 2023We developed a phenotypic screening platform for the functional exploration of dendritic cells (DC). Here, we report a genome-wide CRISPR screen that revealed BCL2 as an...
UNLABELLED
We developed a phenotypic screening platform for the functional exploration of dendritic cells (DC). Here, we report a genome-wide CRISPR screen that revealed BCL2 as an endogenous inhibitor of DC function. Knockout of BCL2 enhanced DC antigen presentation and activation as well as the capacity of DCs to control tumors and to synergize with PD-1 blockade. The pharmacologic BCL2 inhibitors venetoclax and navitoclax phenocopied these effects and caused a cDC1-dependent regression of orthotopic lung cancers and fibrosarcomas. Thus, solid tumors failed to respond to BCL2 inhibition in mice constitutively devoid of cDC1, and this was reversed by the infusion of DCs. Moreover, cDC1 depletion reduced the therapeutic efficacy of BCL2 inhibitors alone or in combination with PD-1 blockade and treatment with venetoclax caused cDC1 activation, both in mice and in patients. In conclusion, genetic and pharmacologic BCL2 inhibition unveils a DC-specific immune checkpoint that restrains tumor immunosurveillance.
SIGNIFICANCE
BCL2 inhibition improves the capacity of DCs to stimulate anticancer immunity and restrain cancer growth in an immunocompetent context but not in mice lacking cDC1 or mature T cells. This study indicates that BCL2 blockade can be used to sensitize solid cancers to PD-1/PD-L1-targeting immunotherapy. This article is featured in Selected Articles from This Issue, p. 2293.
Topics: Humans; Animals; Mice; Dendritic Cells; Programmed Cell Death 1 Receptor; Monitoring, Immunologic; Mice, Knockout; Neoplasms; Antineoplastic Agents; Proto-Oncogene Proteins c-bcl-2
PubMed: 37623817
DOI: 10.1158/2159-8290.CD-22-1338 -
Science Immunology Jul 2023T cell responses against infections and cancer are directed by conventional dendritic cells (cDCs) in lymph nodes distant from the site of challenge. Migratory cDCs,...
T cell responses against infections and cancer are directed by conventional dendritic cells (cDCs) in lymph nodes distant from the site of challenge. Migratory cDCs, which travel from the tissue to the lymph node, not only drive initial T cell activation but also transfer antigen to lymph node-resident cDCs. These resident cells have essential roles defining the character of the resulting T cell response; however, it is unknown how they can appropriately process and present antigens to suitably direct responses given their spatial separation. Here, using a novel strain of influenza A and a modified melanoma model, we show that tissue and lymph node cDC activation is harmonized and that this is driven by cotransfer of contextual cues. In the tumor, incomplete cDC activation in the tumor microenvironment is mirrored by lymph node-resident cDCs, whereas during influenza infection, pathogen-associated molecular patterns cotransferred with antigen drive TLR signaling in resident cDCs and their subsequent robust activation. This cotransfer mechanism explains how individual antigens can be handled distinctly by resident cDCs and how signals driving poor tumoral cDC activation further impact the lymph node. Our findings clarify how tissue context dictates antigenic and, consequently, T cell fate in the lymph node.
Topics: Humans; Influenza, Human; Dendritic Cells; Antigens; Lymph Nodes; T-Lymphocytes
PubMed: 37478193
DOI: 10.1126/sciimmunol.adg8249 -
Nature Cancer Feb 2024Dendritic cells (DCs) are antigen-presenting myeloid cells that regulate T cell activation, trafficking and function. Monocyte-derived DCs pulsed with tumor antigens...
Dendritic cells (DCs) are antigen-presenting myeloid cells that regulate T cell activation, trafficking and function. Monocyte-derived DCs pulsed with tumor antigens have been tested extensively for therapeutic vaccination in cancer, with mixed clinical results. Here, we present a cell-therapy platform based on mouse or human DC progenitors (DCPs) engineered to produce two immunostimulatory cytokines, IL-12 and FLT3L. Cytokine-armed DCPs differentiated into conventional type-I DCs (cDC1) and suppressed tumor growth, including melanoma and autochthonous liver models, without the need for antigen loading or myeloablative host conditioning. Tumor response involved synergy between IL-12 and FLT3L and was associated with natural killer and T cell infiltration and activation, M1-like macrophage programming and ischemic tumor necrosis. Antitumor immunity was dependent on endogenous cDC1 expansion and interferon-γ signaling but did not require CD8 T cell cytotoxicity. Cytokine-armed DCPs synergized effectively with anti-GD2 chimeric-antigen receptor (CAR) T cells in eradicating intracranial gliomas in mice, illustrating their potential in combination therapies.
Topics: Humans; Mice; Animals; Cytokines; Immunotherapy; Dendritic Cells; Neoplasms; Interleukin-12
PubMed: 37996514
DOI: 10.1038/s43018-023-00668-y -
Immunity Aug 2023Unlike macrophage networks composed of long-lived tissue-resident cells within specific niches, conventional dendritic cells (cDCs) that generate a 3D network in lymph...
Unlike macrophage networks composed of long-lived tissue-resident cells within specific niches, conventional dendritic cells (cDCs) that generate a 3D network in lymph nodes (LNs) are short lived and continuously replaced by DC precursors (preDCs) from the bone marrow (BM). Here, we examined whether specific anatomical niches exist within which preDCs differentiate toward immature cDCs. In situ photoconversion and Prtn3-based fate-tracking revealed that the LN medullary cords are preferential entry sites for preDCs, serving as specific differentiation niches. Repopulation and fate-tracking approaches demonstrated that the cDC1 network unfolded from the medulla along the vascular tree toward the paracortex. During inflammation, collective maturation and migration of resident cDC1s to the paracortex created discontinuity in the medullary cDC1 network and temporarily impaired responsiveness. The decrease in local cDC1 density resulted in higher Flt3L availability in the medullary niche, which accelerated cDC1 development to restore the network. Thus, the spatiotemporal development of the cDC1 network is locally regulated in dedicated LN niches via sensing of cDC1 densities.
Topics: Lymph Nodes; Cell Differentiation; Macrophages; Dendritic Cells
PubMed: 37463581
DOI: 10.1016/j.immuni.2023.06.020 -
Nature Communications Jan 2024Toll-like receptor 9 (TLR9) recognizes self-DNA and plays intricate roles in systemic lupus erythematosus (SLE). However, the molecular mechanism regulating the...
Toll-like receptor 9 (TLR9) recognizes self-DNA and plays intricate roles in systemic lupus erythematosus (SLE). However, the molecular mechanism regulating the endosomal TLR9 response is incompletely understood. Here, we report that palmitoyl-protein thioesterase 1 (PPT1) regulates systemic autoimmunity by removing S-palmitoylation from TLR9 in lysosomes. PPT1 promotes the secretion of IFNα by plasmacytoid dendritic cells (pDCs) and TNF by macrophages. Genetic deficiency in or chemical inhibition of PPT1 reduces anti-nuclear antibody levels and attenuates nephritis in B6.Sle1yaa mice. In healthy volunteers and patients with SLE, the PPT1 inhibitor, HDSF, reduces IFNα production ex vivo. Mechanistically, biochemical and mass spectrometry analyses demonstrated that TLR9 is S-palmitoylated at C258 and C265. Moreover, the protein acyltransferase, DHHC3, palmitoylates TLR9 in the Golgi, and regulates TLR9 trafficking to endosomes. Subsequent depalmitoylation by PPT1 facilitates the release of TLR9 from UNC93B1. Our results reveal a posttranslational modification cycle that controls TLR9 response and autoimmunity.
Topics: Humans; Animals; Mice; Autoimmunity; Toll-Like Receptor 9; Lipoylation; Lupus Erythematosus, Systemic; Signal Transduction; Dendritic Cells
PubMed: 38169466
DOI: 10.1038/s41467-023-43650-z -
Nature Mar 2024Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when...
Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone. However, there remains little consensus on the mechanism(s) of response with this combination. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8 T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.
Topics: Animals; Humans; Mice; Antibodies, Monoclonal; Antineoplastic Agents; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Dendritic Cells; Drug Therapy, Combination; Immune Checkpoint Inhibitors; Macrophage Activation; Myeloid Cells; Neoplasms; Receptors, IgG; Receptors, Immunologic; T-Lymphocytes, Regulatory; Tumor Microenvironment; Tumor-Associated Macrophages
PubMed: 38418879
DOI: 10.1038/s41586-024-07121-9 -
Cancer Communications (London, England) Nov 2023Cervical cancer (CC) is the fourth most common cancer in women worldwide. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains...
Interactions of Indoleamine 2,3-dioxygenase-expressing LAMP3 dendritic cells with CD4 regulatory T cells and CD8 exhausted T cells: synergistically remodeling of the immunosuppressive microenvironment in cervical cancer and therapeutic implications.
BACKGROUND
Cervical cancer (CC) is the fourth most common cancer in women worldwide. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains far from satisfactory, necessitating further investigation of the mechanism of CC immune remodeling and exploration of novel treatment targets. This study aimed to investigate the mechanism of CC immune remodeling and explore potential therapeutic targets.
METHODS
We conducted single-cell RNA sequencing on a total of 17 clinical specimens, including normal cervical tissues, high-grade squamous intraepithelial lesions, and CC tissues. To validate our findings, we conducted multicolor immunohistochemical staining of CC tissues and constructed a subcutaneous tumorigenesis model in C57BL/6 mice using murine CC cell lines (TC1) to evaluate the effectiveness of combination therapy involving indoleamine 2,3-dioxygenase 1 (IDO1) inhibition and immune checkpoint blockade (ICB). We used the unpaired two-tailed Student's t-test, Mann-Whitney test, or Kruskal-Wallis test to compare continuous data between two groups and one-way ANOVA with Tukey's post hoc test to compare data between multiple groups.
RESULTS
Malignant cervical epithelial cells did not manifest noticeable signs of tumor escape, whereas lysosomal-associated membrane protein 3-positive (LAMP3 ) dendritic cells (DCs) in a mature state with immunoregulatory roles were found to express IDO1 and affect tryptophan metabolism. These cells interacted with both tumor-reactive exhausted CD8 T cells and CD4 regulatory T cells, synergistically forming a vicious immunosuppressive cycle and mediating CC immune escape. Further validation through multicolor immunohistochemical staining showed co-localization of neoantigen-reactive T cells (CD3 , CD4 /CD8 , and PD-1 ) and LAMP3 DCs (CD80 and PD-L1 ). Additionally, a combination of the IDO1 inhibitor with an ICB agent significantly reduced tumor volume in the mouse model of CC compared with an ICB agent alone.
CONCLUSIONS
Our study suggested that a combination treatment consisting of targeting IDO1 and ICB agent could improve the therapeutic efficacy of current CC immunotherapies. Additionally, our results provided crucial insights for designing drugs and conducting future clinical trials for CC.
Topics: Animals; Female; Humans; Mice; CD8-Positive T-Lymphocytes; Dendritic Cells; Indoleamine-Pyrrole 2,3,-Dioxygenase; Lysosomal Membrane Proteins; Mice, Inbred C57BL; Neoplasm Proteins; T-Lymphocytes, Regulatory; Tumor Microenvironment; Uterine Cervical Neoplasms
PubMed: 37794698
DOI: 10.1002/cac2.12486 -
Nature Immunology Aug 2023High-dimensional approaches have revealed heterogeneity amongst dendritic cells (DCs), including a population of transitional DCs (tDCs) in mice and humans. However, the...
High-dimensional approaches have revealed heterogeneity amongst dendritic cells (DCs), including a population of transitional DCs (tDCs) in mice and humans. However, the origin and relationship of tDCs to other DC subsets has been unclear. Here we show that tDCs are distinct from other well-characterized DCs and conventional DC precursors (pre-cDCs). We demonstrate that tDCs originate from bone marrow progenitors shared with plasmacytoid DCs (pDCs). In the periphery, tDCs contribute to the pool of ESAM type 2 DCs (DC2s), and these DC2s have pDC-related developmental features. Different from pre-cDCs, tDCs have less turnover, capture antigen, respond to stimuli and activate antigen-specific naïve T cells, all characteristics of differentiated DCs. Different from pDCs, viral sensing by tDCs results in IL-1β secretion and fatal immune pathology in a murine coronavirus model. Our findings suggest that tDCs are a distinct pDC-related subset with a DC2 differentiation potential and unique proinflammatory function during viral infections.
Topics: Animals; Mice; Antiviral Agents; Bone Marrow; Cell Differentiation; Dendritic Cells
PubMed: 37414907
DOI: 10.1038/s41590-023-01545-7 -
The Journal of Experimental Medicine Sep 2023Inborn errors of the NF-κB pathways underlie various clinical phenotypes in humans. Heterozygous germline loss-of-expression and loss-of-function mutations in RELA...
Inborn errors of the NF-κB pathways underlie various clinical phenotypes in humans. Heterozygous germline loss-of-expression and loss-of-function mutations in RELA underlie RELA haploinsufficiency, which results in TNF-dependent chronic mucocutaneous ulceration and autoimmune hematological disorders. We here report six patients from five families with additional autoinflammatory and autoimmune manifestations. These patients are heterozygous for RELA mutations, all of which are in the 3' segment of the gene and create a premature stop codon. Truncated and loss-of-function RelA proteins are expressed in the patients' cells and exert a dominant-negative effect. Enhanced expression of TLR7 and MYD88 mRNA in plasmacytoid dendritic cells (pDCs) and non-pDC myeloid cells results in enhanced TLR7-driven secretion of type I/III interferons (IFNs) and interferon-stimulated gene expression in patient-derived leukocytes. Dominant-negative mutations in RELA thus underlie a novel form of type I interferonopathy with systemic autoinflammatory and autoimmune manifestations due to excessive IFN production, probably triggered by otherwise non-pathogenic TLR ligands.
Topics: Humans; Autoimmunity; Dendritic Cells; Interferon Type I; NF-kappa B; Toll-Like Receptor 7; Transcription Factor RelA
PubMed: 37273177
DOI: 10.1084/jem.20212276