scholarly journals Microbial Antigen-Presenting Extracellular Vesicles Derived from Genetically Modified Tumor Cells Promote Antitumor Activity of Dendritic Cells

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 57
Author(s):  
Tomoko Ito ◽  
Kikuya Sugiura ◽  
Aya Hasegawa ◽  
Wakana Ouchi ◽  
Takayuki Yoshimoto ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antitumor Activity ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Ternary Complex ◽  
Binary Complex ◽  
Mouse Bone Marrow ◽  
Bacterial Antigen ◽  
Tumor Vaccines ◽  
Antigen Presenting

Tumor-derived extracellular vesicles (EVs), as tumor vaccines, carry tumor-associated antigens (TAAs), and were expected to transfer TAAs to antigen-presenting cells. However, treatment with tumor-derived EVs exhibited no obvious antitumor effect on the established tumors, likely due to their immuno-suppressive functions, and also to the poor immunogenicity of TAAs. In order to improve the immune stimulating properties, EVs expressing a highly immunogenic bacterial antigen, 6 kDa early secretory antigenic target (ESAT-6), from Mycobacterium tuberculosis were prepared by genetically modifying the parent tumor cells with a plasmid coding for ESAT-6. Cultured B16 tumor cells were transfected with a ternary complex system consisting of pDNA, polyethylenimine (PEI), and chondroitin sulfate. The cells that were transfected with the ternary complex secreted EVs with a higher number of ESAT-6 epitopes than those transfected by a conventional DNA/PEI binary complex, due to the low cytotoxicity, and durable high expression efficiency of the ternary complex systems. The EVs presenting the ESAT-6 epitope (ESAT-EV) were collected and explored as immune modulatory agents. Dendritic cells (DCs) were differentiated from mouse bone marrow cells and incubated with ESAT-EV. After incubating with the EVs for one day, the DCs expressed a significantly higher level of DC maturation marker, CD86. The DCs treated with ESAT-EV showed a significantly improved antitumor activity in tumor-bearing mice.

scholarly journals Pros and Cons of Antigen-Presenting Cell Targeted Tumor Vaccines

2015 ◽  
Vol 2015 ◽  
pp. 1-18 ◽  
Author(s):  
Cleo Goyvaerts ◽  
Karine Breckpot
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Potential Benefit ◽  
Tumor Vaccines ◽  
Antigen Presenting Cell ◽  
Leading Role ◽  
True Meaning ◽  
Pros And Cons ◽  
Antigen Presenting

In therapeutic antitumor vaccination, dendritic cells play the leading role since they decide if, how, when, and where a potent antitumor immune response will take place. Since the disentanglement of the complexity and merit of different antigen-presenting cell subtypes, antitumor immunotherapeutic research started to investigate the potential benefit of targeting these subtypesin situ. This review will discuss which antigen-presenting cell subtypes are at play and how they have been targeted and finally question the true meaning of targeting antitumor-based vaccines.

scholarly journals Interleukin-12–Activated Natural Killer Cells Recognize B7 Costimulatory Molecules on Tumor Cells and Autologous Dendritic Cells

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 196-206 ◽  
Author(s):  
Anja B. Geldhof ◽  
Muriel Moser ◽  
Laurence Lespagnard ◽  
Kris Thielemans ◽  
Patrick De Baetselier
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Synergistic Effects ◽  
Antigen Presenting Cells ◽  
Interleukin 12 ◽  
Target Cells ◽  
Effector Cells ◽  
Antigen Presenting

Activation of natural killer (NK) cells in the presence of interleukin-12 (IL-12) augments the capacity of these effector cells to recognize B7-1– and B7-2–expressing target cells. These effector cells also efficiently lyse autologous B7-positive progenitor or organ-derived dendritic cells, suggesting a physiologic regulatory pathway between IL-12, NK cells, and B7-expressing antigen-presenting cells. Although IL-12–activated NK cells secreted higher levels of interferon-γ, this cytokine did not play a role in synergistic effects of IL-12 and B7 on NK activation. The B7-counterreceptor was found to be selectively upregulated on IL-2/IL-12 as compared with IL-2–activated NK cells. CD28 is functionally involved in the recognition of B7 on target cells since IL-2/IL-12–activated NK cells derived from CD28 knockout mice were strongly reduced in their capacity to lyse syngeneic B7-positive tumor cells as well as antigen-presenting cells. However, recognition of B7 on allogeneic targets did not require the expression of CD28 on the IL-2/IL-12–activated NK cells. Hence, IL-12 triggers the expression of both CD28-dependent and CD28-independent mechanisms that allow NK cells to eliminate B7-positive target cells including autologous dendritic cells.

scholarly journals miR29a and miR378b Influence CpG-Stimulated Dendritic Cells and Regulate cGAS/STING Pathway

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 197 ◽  
Author(s):  
Abid Ullah Shah ◽  
Yanan Cao ◽  
Naila Siddique ◽  
Jian Lin ◽  
Qian Yang
Keyword(s):  
Dendritic Cells ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Mouse Bone Marrow ◽  
Cytokine Detection ◽  
Sting Pathway ◽  
Factor Α ◽  
Antigen Presenting ◽  
And Control

The Cytosine–phosphate–guanosine (CpG) motif, which is specifically recognized intracellularly by dendritic cells (DCs), plays a crucial role in regulating the innate immune response. MicroRNAs (miRNAs) can strongly influence the antigen-presenting ability of DCs. In this study, we examine the action of miRNAs on CpG-stimulated and control DCs, as well as their effect on cyclic guanosine monophosphate-adenosine monophosphate (GMP–AMP) synthase (cGAS) and the stimulator of interferon genes (STING) signal pathway. Firstly, we selected miRNAs (miR-29a and miR-378b) based on expression in CpG-stimulated mouse bone marrow-derived dendritic cells (BMDCs). Secondly, we investigated the functions of miR-29a and miR-378b on CpG-stimulated and unstimulated BMDCs. The results showed that miR-29a and miR-378b increased expression of both the immunoregulatory DC surface markers (CD86 and CD40) and the immunosuppressive molecule CD273 by DCs. Thirdly, cytokine detection revealed that both miR-29a and miR-378b enhanced interferon-β (IFN-β) expression while suppressing tumor necrosis factor-α (TNF-α) production. Finally, our results suggest that miR-378b can bind TANK-binding kinase binding protein 1 (TBKBP1) to activate the cGAS/STING signaling pathway. By contrast, miR-29a targeted interferon regulatory factor 7 (IRF7) and promoted the expression of STING. Together, our results provide insight into the molecular mechanism of miRNA induction by CpG to regulate DC function.

Lipopolysaccharide-sensitive H+ current in dendritic cells

2012 ◽  
Vol 303 (2) ◽  
pp. C204-C212 ◽  
Author(s):  
Kalina Szteyn ◽  
Wenting Yang ◽  
Evi Schmid ◽  
Florian Lang ◽  
Ekaterina Shumilina
Keyword(s):  
Dendritic Cells ◽  
Reversal Potential ◽  
Charge Compensation ◽  
Outer Wall ◽  
Functional Expression ◽  
Lymphoid Tissues ◽  
Mouse Bone Marrow ◽  
Ros Production ◽  
Whole Cell Patch Clamp ◽  
Antigen Presenting

Dendritic cells (DCs) are the most potent antigen-presenting cells equipped to transport antigens from the periphery to lymphoid tissues and to present them to T cells. Ligation of Toll-like receptor 4 (TLR4), expressed on the DC surface, by lipopolysaccharides (LPS), elements of the Gram-negative bacteria outer wall, induces DC maturation. Initial steps of maturation include stimulation of antigen endocytosis and enhanced reactive oxygen species (ROS) production with eventual downregulation of endocytic capacity in fully matured DCs. ROS production depends on NADPH oxidase (NOX2), the activity of which requires continuous pH and charge compensation. The present study demonstrates, for the first time, the functional expression of voltage-gated proton (Hv1) channels in mouse bone marrow-derived DCs. In whole cell patch-clamp experiments, we recorded Zn2+ (50 μM)-sensitive outwardly rectifying currents activated upon depolarization, which were highly selective for H+, with the reversal potential shift of 38 mV per pH unit. The threshold voltage of activation ( Vthreshold) was dependent on the pH gradient and was close to the empirically predicted Vthreshold for the Hv1 currents. LPS (1 μg/ml) had bimodal effects on Hv1 channels: acute LPS treatment increased Hv1 channel activity, whereas 24 h of LPS incubation significantly inhibited Hv1 currents and decreased ROS production. Activation of H+ currents by acute application of LPS was abolished by PKC inhibitor GFX (10 nM). According to electron current measurements, acute LPS application was associated with increased NOX2 activity.

scholarly journals Interleukin-12–Activated Natural Killer Cells Recognize B7 Costimulatory Molecules on Tumor Cells and Autologous Dendritic Cells

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 196-206 ◽  
Author(s):  
Anja B. Geldhof ◽  
Muriel Moser ◽  
Laurence Lespagnard ◽  
Kris Thielemans ◽  
Patrick De Baetselier
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Synergistic Effects ◽  
Antigen Presenting Cells ◽  
Interleukin 12 ◽  
Target Cells ◽  
Effector Cells ◽  
Antigen Presenting

Abstract Activation of natural killer (NK) cells in the presence of interleukin-12 (IL-12) augments the capacity of these effector cells to recognize B7-1– and B7-2–expressing target cells. These effector cells also efficiently lyse autologous B7-positive progenitor or organ-derived dendritic cells, suggesting a physiologic regulatory pathway between IL-12, NK cells, and B7-expressing antigen-presenting cells. Although IL-12–activated NK cells secreted higher levels of interferon-γ, this cytokine did not play a role in synergistic effects of IL-12 and B7 on NK activation. The B7-counterreceptor was found to be selectively upregulated on IL-2/IL-12 as compared with IL-2–activated NK cells. CD28 is functionally involved in the recognition of B7 on target cells since IL-2/IL-12–activated NK cells derived from CD28 knockout mice were strongly reduced in their capacity to lyse syngeneic B7-positive tumor cells as well as antigen-presenting cells. However, recognition of B7 on allogeneic targets did not require the expression of CD28 on the IL-2/IL-12–activated NK cells. Hence, IL-12 triggers the expression of both CD28-dependent and CD28-independent mechanisms that allow NK cells to eliminate B7-positive target cells including autologous dendritic cells.

scholarly journals Tumor Extracellular Vesicles Regulate Macrophage-Driven Metastasis through CCL5

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3459
Author(s):  
Daniel C. Rabe ◽  
Nykia D. Walker ◽  
Felicia D. Rustandy ◽  
Jessica Wallace ◽  
Jiyoung Lee ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Tumor Metastasis ◽  
Tumor Stroma ◽  
Metastatic Tumor ◽  
Mouse Bone Marrow ◽  
Metastatic Phenotype ◽  
Immune Infiltrate ◽  
Phenotype Analysis

Purpose: To understand how tumor cells alter macrophage biology once they are recruited to triple-negative breast cancer (TNBC) tumors by CCL5. Method: Mouse bone marrow derived macrophage (BMDMs) were isolated and treated with recombinant CCL5 protein alone, with tumor cell conditioned media, or with tumor extracellular vesicles (EVs). Media from these tumor EV-educated macrophages (TEMs) was then used to determine how these macrophages affect TNBC invasion. To understand the mechanism, we assayed the cytokine secretion from these macrophages to determine how they impact tumor cell invasion. Tumor CCL5 expression was varied in tumors to determine its role in regulating macrophage biology through EVs. Results: Tumor EVs are a necessary component for programming naïve macrophages toward a pro-metastatic phenotype. CCL5 expression in the tumor cells regulates both EV biogenesis/secretion/cargo and macrophage EV-education toward a pro-metastatic phenotype. Analysis of the tumor EV-educated macrophages (TEMs) showed secretion of a variety of factors including CXCL1, CTLA-4, IFNG, OPN, HGF, TGFB, and CCL19 capable of remodeling the surrounding tumor stroma and immune infiltrate. Injection of tumor cells with macrophages educated by metastatic tumor cell EVs into mice increased tumor metastasis to the lung. Conclusion: These results demonstrate that tumor-derived EVs are key mediators of macrophage education and likely play a more complex role in modulating tumor therapeutic response by regulating the tumor immune infiltrate.

scholarly journals Antigen-Specific Polyclonal Cytotoxic T Lymphocytes Induced by Fusions of Dendritic Cells and Tumor Cells

2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Shigeo Koido ◽  
Sadamu Homma ◽  
Eiichi Hara ◽  
Yoshihisa Namiki ◽  
Toshifumi Ohkusa ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Lymphocytes ◽  
Immune Responses ◽  
Tumor Cells ◽  
Cytotoxic T Lymphocytes ◽  
Alternative Approach ◽  
Antigen Presenting ◽  
Ctl Induction ◽  
Secondary Lymphoid Organs ◽  
Powerful Strategy

The aim of cancer vaccines is induction of tumor-specific cytotoxic T lymphocytes (CTLs) that can reduce the tumor mass. Dendritic cells (DCs) are potent antigen-presenting cells and play a central role in the initiation and regulation of primary immune responses. Thus, DCs-based vaccination represents a potentially powerful strategy for induction of antigen-specific CTLs. Fusions of DCs and whole tumor cells represent an alternative approach to deliver, process, and subsequently present a broad spectrum of antigens, including those known and unidentified, in the context of costimulatory molecules. Once DCs/tumor fusions have been infused back into patient, they migrate to secondary lymphoid organs, where the generation of antigen-specific polyclonal CTL responses occurs. We will discuss perspectives for future development of DCs/tumor fusions for CTL induction.

Hydrophobic chain modified low molecular weight polyethylenimine for efficient antigen delivery

RSC Advances ◽  
2016 ◽  
Vol 6 (17) ◽  
pp. 13636-13643 ◽  
Author(s):  
Hui Wang ◽  
Jian Chen ◽  
Jiajun Ying ◽  
Yuhong Xu ◽  
Ruilong Sheng
Keyword(s):  
Molecular Weight ◽  
Dendritic Cells ◽  
Tumor Cells ◽  
Low Molecular Weight ◽  
Antigen Delivery ◽  
Therapeutic Vaccines ◽  
Cross Presentation ◽  
Cell Responses ◽  
Hydrophobic Chain ◽  
Antigen Presenting

Developing new therapeutic vaccines to promote antigen cross-presentation in antigen-presenting cells, especially dendritic cells, is regarded as a promising approach to prime antigen-specific T cell responses against tumor cells.

scholarly journals TARM1 contributes to development of arthritis by activating dendritic cells through recognition of collagens

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rikio Yabe ◽  
Soo-Hyun Chung ◽  
Masanori A. Murayama ◽  
Sachiko Kubo ◽  
Kenji Shimizu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Bone Marrow Cells ◽  
Dendritic Cell Maturation ◽  
Mouse Bone Marrow ◽  
Gm Csf ◽  
Good Target ◽  
Antigen Presenting ◽  
Dc Maturation

AbstractTARM1 is a member of the leukocyte immunoglobulin-like receptor family and stimulates macrophages and neutrophils in vitro by associating with FcRγ. However, the function of this molecule in the regulation of the immune system is unclear. Here, we show that Tarm1 expression is elevated in the joints of rheumatoid arthritis mouse models, and the development of collagen-induced arthritis (CIA) is suppressed in Tarm1–/– mice. T cell priming against type 2 collagen is suppressed in Tarm1–/– mice and antigen-presenting ability of GM-CSF-induced dendritic cells (GM-DCs) from Tarm1–/– mouse bone marrow cells is impaired. We show that type 2 collagen is a functional ligand for TARM1 on GM-DCs and promotes DC maturation. Furthermore, soluble TARM1-Fc and TARM1-Flag inhibit DC maturation and administration of TARM1-Fc blocks the progression of CIA in mice. These results indicate that TARM1 is an important stimulating factor of dendritic cell maturation and could be a good target for the treatment of autoimmune diseases.

Surfactant protein D enhances bacterial antigen presentation by bone marrow-derived dendritic cells

2001 ◽  
Vol 281 (6) ◽  
pp. L1453-L1463 ◽  
Author(s):  
Karen G. Brinker ◽  
Emily Martin ◽  
Paul Borron ◽  
Elahe Mostaghel ◽  
Carolyn Doyle ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Dendritic Cells ◽  
Antigen Presentation ◽  
Surfactant Protein ◽  
Innate Immune ◽  
Surfactant Protein D ◽  
Mouse Bone Marrow ◽  
Bacterial Antigen ◽  
Dependent Manner

Surfactant protein (SP) D functions as a soluble pattern recognition molecule to mediate the clearance of pathogens by phagocytes in the innate immune response. We hypothesize that SP-D may also interact with dendritic cells, the most potent antigen presenting cell, to enhance uptake and presentation of bacterial antigens. Using mouse bone marrow-derived dendritic cells, we show that SP-D binds to immature dendritic cells in a dose-, carbohydrate-, and calcium-dependent manner, whereas SP-D binding to mature dendritic cells is reduced. SP-D also binds to Escherichia coli HB101 and enhances its association with dendritic cells. Additionally, SP-D enhances the antigen presentation of an ovalbumin fusion protein expressed in E. coli HB101 to ovalbumin-specific major histocompatibility complex class II T cell hybridomas. The enhancement of antigen presentation by SP-D is dose dependent and is not shared by other collectin-like proteins tested. These studies demonstrate that SP-D augments antigen presentation by dendritic cells and suggest that innate immune molecules such as SP-D may help initiate an adaptive immune response for the purpose of resolving an infection.

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