scholarly journals Network and systems based re-engineering of dendritic cells with non-coding RNAs for cancer immunotherapy

2020 ◽  
Author(s):  
Xin Lai ◽  
Florian S. Dreyer ◽  
Martina Cantone ◽  
Martin Eberhardt ◽  
Kerstin F. Gerer ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Rna Sequencing ◽  
Therapeutic Potential ◽  
Mirna Gene ◽  
Sequencing Data ◽  
Dc Optimization ◽  
Signalling Network ◽  
Differentially Expressed Mirnas ◽  
Antigen Presenting

AbstractDendritic cells (DCs) are professional antigen-presenting cells that induce and regulate adaptive immunity by presenting antigens to T cells. Due to their coordinative role in adaptive immune responses, DCs have been used as cell-based therapeutic vaccination against cancer. The capacity of DCs to induce a therapeutic immune response can be enhanced by re-wiring of cellular signalling pathways with microRNAs (miRNAs). Since the activation and maturation of DCs is controlled by an interconnected signalling network, we deploy an approach that combines RNA sequencing data and systems biology methods to delineate miRNA-based strategies that enhance DC-elicited immune responses.Through RNA sequencing of IKKβ-matured DCs that are currently being tested in a clinical trial on therapeutic anti-cancer vaccination, we identified 44 differentially expressed miRNAs. According to a network analysis, most of these miRNAs regulate targets that are linked to immune pathways, such as cytokine and interleukin signalling. We employed a network topology-oriented scoring model to rank the miRNAs, analysed their impact on immunogenic potency of DCs, and identified dozens of promising miRNA candidates with miR-15a and miR-16 as the top ones. The results of our analysis are incorporated in a database which constitutes a tool to identify DC-relevant miRNA-gene interactions with therapeutic potential (www.synmirapy.net/dc-optimization).

scholarly journals Transcriptional Analysis of TH2 Primed Dendritic Cells and T cells

2021 ◽  
Author(s):  
◽  
Cynthia Morgan
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cell Surface ◽  
Immune Responses ◽  
Rna Sequencing ◽  
Transcriptional Analysis ◽  
Th2 Cells ◽  
Nippostrongylus Brasiliensis ◽  
Sequencing Data ◽  
Th2 Response

<p><b>Allergy is a condition affecting between 10 and 30% of the world’s population, with incidence rising every year. It is primarily mediated by THelper (TH) 0 cells reacting to an ordinarily harmless environmental antigen to induce an adaptive TH2 response. TH0 cells are presented the antigen by dendritic cells (DC), the immune systems most proficient antigen presenting cell, which act as the bridge between the innate and adaptive immune system. Dendritic cells specific to this study termed Triple Negative (TN) and CD11b+ are able to prime T cells to become TH2 cells, but current research has been unable to fully determine the proteins that mediate this TH2 priming. TN and CD11b+ DC exhibit transcriptional and functional distinction within the TH2 response, but the individual functions they take on during TH2 responses have not fully been determined. Some evidence suggests that the cell surface protein OX40L and the secreted protein TSLP are capable of inducing TH2 priming, but this is not conserved across all TH2 models. In an effort to determine other specific proteins that induce TH2 priming, RNA-sequencing has been utilized on TN and CD11b+ dendritic cells in TH2 inducing conditions. This thesis aims to analyse RNA-sequencing data generated from purified TH2 antigen positive TN and CD11b+ dendritic cells that have taken up a TH2-inducing stimulus – fluorescently labelled (AF488) non-viable Nippostrongylus brasiliensis. Due to the majority of DC-TH0 interactions occurring at the cell surface interface, the bioinformatic analysis was focused on genes belonging to the surface and secreted compartments.</b></p> <p>Here I show that AF488-Nippostrongylus brasiliensis positive TN and CD11b+ DC are transcriptionally distinct from each other. Functional roles of differentially expressed genes (DEG) were also markedly distinct. Superfamily analysis revealed TN genes associated with signal transduction and proteases, whereas CD11b+ DEG were linked to cell adhesion and immune responses. This suggests that the different DC subsets have different roles in an immune response, and potentially different roles in the induction of TH2 immune responses. Network analysis of DEG from DC subsets and proteins expressed by TH0 and TH2 cell surfaces identified over 300 predicted interactions. Notably, 33 identified were known interactions – validating the bioinformatic methods used. Finally, I have been developing a method to assess novel interactions via flow cytometry methods that allows detection of binding and identification of the cell population that is bound. This has shown promise with the detection of generated proteins bound to TN and CD11b+ DC during TH2 stimulating conditions, paving the way for future novel interaction analyses.</p>

scholarly journals Dendritic Cells The Tumor Microenvironment and the Challenges for an Effective Antitumor Vaccination

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Fabian Benencia ◽  
Leslee Sprague ◽  
John McGinty ◽  
Michelle Pate ◽  
Maria Muccioli
Keyword(s):  
Clinical Trials ◽  
Dendritic Cells ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Immune Cells ◽  
Therapeutic Potential ◽  
Human Cancer ◽  
Dc Vaccines ◽  
Tumor Clearance ◽  
Antigen Presenting

Many clinical trials have been carried out or are in progress to assess the therapeutic potential of dendritic-cell- (DC-) based vaccines on cancer patients, and recently the first DC-based vaccine for human cancer was approved by the FDA. Herewith, we describe the general characteristics of DCs and different strategies to generate effective antitumor DC vaccines. In recent years, the relevance of the tumor microenvironment in the progression of cancer has been highlighted. It has been shown that the tumor microenvironment is capable of inactivating various components of the immune system responsible for tumor clearance. In particular, the effect of the tumor microenvironment on antigen-presenting cells, such as DCs, does not only render these immune cells unable to induce specific immune responses, but also turns them into promoters of tumor growth. We also describe strategies likely to increase the efficacy of DC vaccines by reprogramming the immunosuppressive nature of the tumor microenvironment.

scholarly journals Transcriptional Analysis of TH2 Primed Dendritic Cells and T cells

2021 ◽  
Author(s):  
◽  
Cynthia Morgan
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cell Surface ◽  
Immune Responses ◽  
Rna Sequencing ◽  
Transcriptional Analysis ◽  
Th2 Cells ◽  
Nippostrongylus Brasiliensis ◽  
Sequencing Data ◽  
Th2 Response

<p><b>Allergy is a condition affecting between 10 and 30% of the world’s population, with incidence rising every year. It is primarily mediated by THelper (TH) 0 cells reacting to an ordinarily harmless environmental antigen to induce an adaptive TH2 response. TH0 cells are presented the antigen by dendritic cells (DC), the immune systems most proficient antigen presenting cell, which act as the bridge between the innate and adaptive immune system. Dendritic cells specific to this study termed Triple Negative (TN) and CD11b+ are able to prime T cells to become TH2 cells, but current research has been unable to fully determine the proteins that mediate this TH2 priming. TN and CD11b+ DC exhibit transcriptional and functional distinction within the TH2 response, but the individual functions they take on during TH2 responses have not fully been determined. Some evidence suggests that the cell surface protein OX40L and the secreted protein TSLP are capable of inducing TH2 priming, but this is not conserved across all TH2 models. In an effort to determine other specific proteins that induce TH2 priming, RNA-sequencing has been utilized on TN and CD11b+ dendritic cells in TH2 inducing conditions. This thesis aims to analyse RNA-sequencing data generated from purified TH2 antigen positive TN and CD11b+ dendritic cells that have taken up a TH2-inducing stimulus – fluorescently labelled (AF488) non-viable Nippostrongylus brasiliensis. Due to the majority of DC-TH0 interactions occurring at the cell surface interface, the bioinformatic analysis was focused on genes belonging to the surface and secreted compartments.</b></p> <p>Here I show that AF488-Nippostrongylus brasiliensis positive TN and CD11b+ DC are transcriptionally distinct from each other. Functional roles of differentially expressed genes (DEG) were also markedly distinct. Superfamily analysis revealed TN genes associated with signal transduction and proteases, whereas CD11b+ DEG were linked to cell adhesion and immune responses. This suggests that the different DC subsets have different roles in an immune response, and potentially different roles in the induction of TH2 immune responses. Network analysis of DEG from DC subsets and proteins expressed by TH0 and TH2 cell surfaces identified over 300 predicted interactions. Notably, 33 identified were known interactions – validating the bioinformatic methods used. Finally, I have been developing a method to assess novel interactions via flow cytometry methods that allows detection of binding and identification of the cell population that is bound. This has shown promise with the detection of generated proteins bound to TN and CD11b+ DC during TH2 stimulating conditions, paving the way for future novel interaction analyses.</p>

scholarly journals Tonsillar Cancer with High CD8+ T-Cell Infiltration Features Increased Levels of Dendritic Cells and Transcriptional Regulation Associated with an Inflamed Tumor Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5341
Author(s):  
David Gomez Jimenez ◽  
Aastha Sobti ◽  
David Askmyr ◽  
Christina Sakellariou ◽  
Sofia Carreira Santos ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Rna Sequencing ◽  
Antigen Presenting Cells ◽  
Cd8 T Cell ◽  
Sequencing Data ◽  
Tonsillar Cancer ◽  
Antigen Presenting

Human papillomavirus (HPV) is the main causal agent of tonsillar cancer (TC) and HPV+ TC has a favorable prognosis compared to HPV– disease. In this study, we examined aspects of the tumor microenvironment of TC, focusing on T-cells, dendritic cells (DC), and macrophages. Fresh biopsies of TC and the contralateral healthy tonsil (HT) were obtained from 20 patients, analyzed by multiparameter flow cytometry, and assessed against a detailed HPV-status. Additionally, RNA-sequencing data from 38 TC samples available in the public database, The Cancer Genome Atlas (TCGA), were explored, focusing on the same leukocyte populations. HPV+ TC featured increased levels of CD8+ T-cells and antigen-presenting cells (cf. HPV– TC and HT, respectively). In HPV+ TC, CD8+ T-cell frequencies correlated to DC levels independently of tumor stage, HPV 16 copy number, and E7 oncogene expression as well as frequencies of other leukocytes. Similarly, RNA sequencing data were explored by dividing the HPV+ TCs according to predefined CD8+ T-cell scores in silico. Higher levels of genes expressed by antigen-presenting cells and effector T-cells, such as immune checkpoints and cytokines, were detected in the CD8HIGH HPV+ TC samples (cf. CD8LOW HPV+ TC). In conclusion, CD8HIGH HPV+ TC displays a unique inflammatory profile associated with increased effector T-cell functions and the presence of antigen-presenting cells in the tumor microenvironment. Further studies are warranted to assess if this information can be used on an individual basis to aid in prognosis and treatment decisions.

scholarly journals Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury

2021 ◽  
Vol 22 (10) ◽  
pp. 5386
Author(s):  
Maria Namwanje ◽  
Bijay Bisunke ◽  
Thomas V. Rousselle ◽  
Gene G. Lamanilao ◽  
Venkatadri S. Sunder ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Mitochondrial Dynamics ◽  
Graft Loss ◽  
Kidney Injury ◽  
Adaptive Immune ◽  
Consumption Rates ◽  
Regulatory Phenotype

Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with rapamycin (10 ng/mL) for 1 h before LPS. In contrast, rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of rapamycin-treated DCs to WT recipients 24 h before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/mL) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury.

scholarly journals IMMU-35. TRANSCRIPTIONALLY DEFINED IMMUNE CONTEXTURE IN HUMAN GLIOMAS AT SINGLE-CELL RESOLUTION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii112-ii112
Author(s):  
Pravesh Gupta ◽  
Minghao Dang ◽  
Krishna Bojja ◽  
Tuan Tran M ◽  
Huma Shehwana ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
Immune Cell ◽  
Wild Type ◽  
Sequencing Data ◽  
Human Gliomas ◽  
Cell Clusters ◽  
Recurrent Gliomas ◽  
Antigen Presenting

Abstract The brain tumor immune microenvironment (TIME) continuously evolves during glioma progression and a comprehensive understanding of the glioma-centric immune cell repertoire beyond a priori cell types and/or states is uncharted. Consequently, we performed single-cell RNA-sequencing on ~123,000 tumor-derived immune cells from 17-pathologically stratified, IDH (isocitrate dehydrogenase)-differential primary, recurrent human gliomas, and non-glioma brains. Our analysis delineated predominant 34-myeloid cell clusters (~75%) over 28-lymphoid cell clusters (~25%) reflecting enormous heterogeneity within and across gliomas. The glioma immune diversity spanned functionally imprinted phagocytic, antigen-presenting, hypoxia, angiogenesis and, tumoricidal myeloid to classical cytotoxic lymphoid subpopulations. Specifically, IDH-mutant gliomas were enriched for brain-resident microglial subpopulations in contrast to enhanced bone barrow-derived infiltrates in IDH-wild type, especially in a recurrent setting. Microglia attrition in IDH-wild type -primary and -recurrent gliomas were concomitant with invading monocyte-derived cells with semblance to dendritic cell and macrophage/microglia like transcriptomic features. Additionally, microglial functional diversification was noted with disease severity and mostly converged to inflammatory states in IDH-wild type recurrent gliomas. Beyond dendritic cells, multiple antigen-presenting cellular states expanded with glioma severity especially in IDH-wild type primary and recurrent- gliomas. Furthermore, we noted differential microglia and dendritic cell inherent antigen presentation axis viz, osteopontin, and classical HLAs in IDH subtypes and, glioma-wide non-PD1 checkpoints associations in T cells like Galectin9 and Tim-3. As a general utility, our immune cell deconvolution approach with single-cell-matched bulk RNA sequencing data faithfully resolved 58-cell states which provides glioma specific immune reference for digital cytometry application to genomics datasets. Resultantly, we identified prognosticator immune cell-signatures from TCGA cohorts as one of many potential immune responsiveness applications of the curated signatures for basic and translational immune-genomics efforts. Thus, we not only provide an unprecedented insight of glioma TIME but also present an immune data resource that can be exploited to guide pragmatic glioma immunotherapy designs.

Functional domains of HSP70 stimulate generation of cytokines and chemokines, maturation of dendritic cells and adjuvanticity

2004 ◽  
Vol 32 (4) ◽  
pp. 629-632 ◽  
Author(s):  
T. Lehner ◽  
Y. Wang ◽  
T. Whittall ◽  
E. McGowan ◽  
C.G. Kelly ◽  
...  
Keyword(s):  
Amino Acids ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Cd40 Ligand ◽  
Interleukin 12 ◽  
Cytokines And Chemokines ◽  
Cc Chemokines ◽  
Factor Α ◽  
Antigen Presenting ◽  
Necrosis Factor

Microbial HSP70 (heat-shock protein 70) consists of three functionally distinct domains: an N-terminal 44 kDa ATPase portion (amino acids 1–358), followed by an 18 kDa peptide-binding domain (amino acids 359–494) and a C-terminal 10 kDa fragment (amino acids 495–609). Immunological functions of these three different domains in stimulating monocytes and dendritic cells have not been fully defined. However, the C-terminal portion (amino acids 359–610) stimulates the production of CC chemokines, IL-12 (interleukin-12), TNFα(tumour necrosis factor α), NO and maturation of dendritic cells and also functions as an adjuvant in the induction of immune responses. In contrast, the ATPase domain of microbial HSP70 mostly lacks these functions. Since the receptor for HSP70 is CD40, which with its CD40 ligand constitutes a major co-stimulatory pathway in the interaction between antigen-presenting cells and T-cells, HSP70 may function as an alternative ligand to CD40L. HSP70–CD40 interaction has been demonstrated in non-human primates to play a role in HIV infection, in protection against Mycobacterium tuberculosis and in conversion of tolerance to immunity.

scholarly journals Regulation of the Migration of Distinct Dendritic Cell Subsets

2021 ◽  
Vol 9 ◽  
Author(s):  
Meng Feng ◽  
Shuping Zhou ◽  
Yong Yu ◽  
Qinghong Su ◽  
Xiaofan Li ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Immune Responses ◽  
The Body ◽  
Inflammatory Factors ◽  
Pathogenic Microorganisms ◽  
Migration Patterns ◽  
Dendritic Cell Subsets ◽  
And Migration ◽  
Antigen Presenting

Dendritic cells (DCs), a class of antigen-presenting cells, are widely present in tissues and apparatuses of the body, and their ability to migrate is key for the initiation of immune activation and tolerogenic immune responses. The importance of DCs migration for their differentiation, phenotypic states, and immunologic functions has attracted widespread attention. In this review, we discussed and compared the chemokines, membrane molecules, and migration patterns of conventional DCs, plasmocytoid DCs, and recently proposed DC subgroups. We also review the promoters and inhibitors that affect DCs migration, including the hypoxia microenvironment, tumor microenvironment, inflammatory factors, and pathogenic microorganisms. Further understanding of the migration mechanisms and regulatory factors of DC subgroups provides new insights for the treatment of diseases, such as infection, tumors, and vaccine preparation.

scholarly journals Evaluation of Feline Monocyte-Derived Dendritic Cells Loaded with Internally Inactivated Virus as a Vaccine against Feline Immunodeficiency Virus

2008 ◽  
Vol 15 (3) ◽  
pp. 452-459 ◽  
Author(s):  
Giulia Freer ◽  
Donatella Matteucci ◽  
Paola Mazzetti ◽  
Francesca Tarabella ◽  
Valentina Catalucci ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Immune Functions ◽  
Peripheral Blood Mononuclear ◽  
Challenge Virus ◽  
Homologous Virus ◽  
Antibody Titers ◽  
Cellular Immune ◽  
Antigen Presenting

ABSTRACT Dendritic cells are the only antigen-presenting cells that can present exogenous antigens to both helper and cytolytic T cells and prime Th1-type or Th2-type cellular immune responses. Given their unique immune functions, dendritic cells are considered attractive “live adjuvants” for vaccination and immunotherapy against cancer and infectious diseases. The present study was carried out to assess whether the reinjection of autologous monocyte-derived dendritic cells loaded with an aldithriol-2-inactivated primary isolate of feline immune deficiency virus (FIV) was able to elicit protective immune responses against the homologous virus in naive cats. Vaccine efficacy was assessed by monitoring immune responses and, finally, by challenge with the homologous virus of vaccinated, mock-vaccinated, and healthy cats. The outcome of challenge was followed by measuring cellular and antibody responses and viral and proviral loads and quantitating FIV by isolation and a count of CD4+/CD8+ T cells in blood. Vaccinated animals exhibited clearly evident FIV-specific peripheral blood mononuclear cell proliferation and antibody titers in response to immunization; however, they became infected with the challenge virus at rates comparable to those of control animals.

Manipulating dendritic cell biology for the active immunotherapy of cancer

Blood ◽  
2004 ◽  
Vol 104 (8) ◽  
pp. 2235-2246 ◽  
Author(s):  
David W. O'Neill ◽  
Sylvia Adams ◽  
Nina Bhardwaj
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Cell Biology ◽  
Active Immunotherapy ◽  
Transplantation Tolerance ◽  
Chronic Infections ◽  
Immunotherapy Of Cancer ◽  
Antigen Presenting ◽  
And Control ◽  
New Strategies

Abstract Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that have an unequaled capacity to initiate primary immune responses, including tolerogenic responses. Because of the importance of DCs in the induction and control of immunity, an understanding of their biology is central to the development of potent immunotherapies for cancer, chronic infections, autoimmune disease, and induction of transplantation tolerance. This review discusses recent advances in DC research and the application of this knowledge toward new strategies for the clinical manipulation of DCs for cancer immunotherapy.

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