Sensitivity of Dendritic Cells to Microenvironment Signals

Motta, Juliana María; Rumjanek, Vivian M.

doi:10.1155/2016/4753607

Cited by 34 publications

(27 citation statements)

References 81 publications

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“…DCs are antigen-presenting cells that are able to capture self and pathogenic antigens, process them, and present them, conjugated with major histocompatibility complexes, to T cells [ 33 , 34 ]. They also regulate the function of T-lymphocyte populations and are capable of activating regulatory T cells and inducing apoptosis of autoreactive T cells [ 33 , 34 ]. Different DC subsets with different profiles exert specific pro-inflammatory or regulatory functions.…”

Section: Resultsmentioning

confidence: 99%

“…Different DC subsets with different profiles exert specific pro-inflammatory or regulatory functions. During the differentiation process from monocytes, iDCs downregulate CD14 and begin expressing CD1a, a surface molecule that is not expressed in any other monocyte-derived population and is implicated in the antigen presentation process [ 34 ]. Typically, fully differentiated DCs are CD14 − CD1a + (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…CD1a is tightly linked to the antigen-presenting function of DC. Presumably, these “ASC-educated” CD14 + CD1a − mDCs have been modified from activated antigen-presenting cells to phagocytic and regulatory cells [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

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Human adipose mesenchymal stem cells modulate myeloid cells toward an anti-inflammatory and reparative phenotype: role of IL-6 and PGE2

Ortiz-Virumbrales¹,

Menta²,

Pérez³

et al. 2020

Stem Cell Res Ther

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Background Mesenchymal stem cells (MSCs) activate the endogenous immune regulatory system, inducing a therapeutic effect in recipients. MSCs have demonstrated the ability to modulate the differentiation of myeloid cells toward a phagocytic and anti-inflammatory profile. Allogeneic, adipose-derived MSCs (ASCs) have been investigated for the management of complex perianal fistula, with darvadstrocel being the first ASC therapy approved in Europe in March 2018. Additionally, ASCs are being explored as a potential treatment in other indications. Yet, despite these clinical advances, their mechanism of action is only partially understood. Methods Freshly isolated human monocytes from the peripheral blood were differentiated in vitro toward M0 non-polarized macrophages (Mphs), M1 pro-inflammatory Mphs, M2 anti-inflammatory Mphs, or mature dendritic cells (mDCs) in the presence or absence of ASCs, in non-contact conditions. The phenotype and function of the differentiated myeloid populations were determined by flow cytometry, and their secretome was analyzed by OLINK technology. We also investigated the capacity of ASCs to modulate the phenotype and function of terminally differentiated M1 Mphs. The role of soluble factors interleukin (IL)-6 and prostaglandin E2 (PGE2) on the ability of ASCs to modulate myeloid cells was assessed using neutralization assays, CRISPR/Cas9 knock-down of cyclooxygenase 2 (COX-2), and ASC-conditioned medium assays using pro-inflammatory stimulus. Results Co-culture of monocytes in the presence of ASCs resulted in the polarization of Mphs and mDCs toward an anti-inflammatory and phagocytic phenotype. This was characterized by an increase in phagocytic receptors on the cell surface of Mphs (M0, M1, and M2) and mDCs, as well as modulation of chemokine receptors and reduced expression of pro-inflammatory, co-stimulatory molecules. ASCs also modulated the secretome of Mphs and mDCs, demonstrated by reduced expression of pro-inflammatory factors and increased expression of anti-inflammatory and reparative factors. Chemical inhibition of PGE2 with indomethacin abolished this modulatory effect, whereas treatment with a neutralizing anti-IL-6 antibody resulted in a partial abolishment. The knock-down of COX-2 in ASCs and the use of IL-1β-activated ASC-conditioned media confirmed the key role of PGE2 in ASC-mediated myeloid modulation. In our in vitro experimental settings, ASCs failed to modulate the phenotype and function of terminally polarized M1 Mphs. Conclusions The results demonstrate that ASCs are able to modulate the in vitro differentiation of myeloid cells toward an anti-inflammatory and reparative profile. This modulatory effect was mediated mainly by PGE2 and, to a lesser extent, IL-6.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Human adipose mesenchymal stem cells modulate myeloid cells toward an anti-inflammatory and reparative phenotype: role of IL-6 and PGE2

Ortiz-Virumbrales¹,

Menta²,

Pérez³

et al. 2020

Stem Cell Res Ther

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“…DCs play an important role in initiating both innate and adaptive immune responses. However, the tumor microenvironment disrupts DC maturation and activation, resulting in the formation of DCs with immunosuppressive potential, as seen in breast cancer and HCC [31].…”

Section: Hcc-derived Exosomes Are Critical For Immune Escapementioning

confidence: 99%

HCC-Derived Exosomes: Critical Player and Target for Cancer Immune Escape

Han

Zhao

et al. 2019

Cells

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Hepatocellular carcinoma (HCC) is a primary malignancy of the liver, and currently the second most common cause of cancer-related deaths worldwide with increasing incidence and poor prognosis. Exosomes are now considered as important mediators of host anti-tumor immune response as well as tumor cell immune escape. HCC-derived exosomes have been shown to attenuate the cytotoxicity of T-cells and NK cells, and promote the immuno-suppressive M2 macrophages, N2 neutrophils, and Bregs. These exosomes harbor several immune-related non-coding RNAs and proteins that drive immune-escape and tumor progression, and thus may serve as potential diagnostic biomarkers and therapeutic targets for HCC. In a previous study, we identified miR146a as an exosomal factor that promotes M2-polarization and suppresses the anti-HCC function of T-cells. In this review, we summarized the role of tumor-derived exosomes and their key components in mediating tumor immune escape during HCC development.

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“…Tumors generally tend to be naturally infiltrated with effector lymphocytes and are considered to be “immunogenic” neoplasms. However, instead of being infiltrated with large numbers of effector lymphocytes, PDAC is characterized by a highly immunosuppressive TME, which comprises cancer cells as well as immunosuppressive regulatory cells including cancer-associated fibroblasts,[ 9 ] tolerogenic dendritic cells,[ 10 ] myeloid-derived suppression cells,[ 11 ] tumor-associated macrophages,[ 12 ] and regulatory T cells. [ 13 ] As a result, PDACs are generally considered to be “non-immunogenic” neoplasms and show weak antitumor responses induced by immune-based therapies such as vaccines.…”

Section: Introductionmentioning

confidence: 99%

A practical approach to pancreatic cancer immunotherapy using resected tumor lysate vaccines processed to express α-gal epitopes

et al. 2017

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ObjectivesSingle-agent immunotherapy is ineffective against poorly immunogenic cancers, including pancreatic ductal adenocarcinoma (PDAC). The aims of this study were to demonstrate the feasibility of production of novel autologous tumor lysate vaccines from resected PDAC tumors, and verify vaccine safety and efficacy.MethodsFresh surgically resected tumors obtained from human patients were processed to enzymatically synthesize α-gal epitopes on the carbohydrate chains of membrane glycoproteins. Processed membranes were analyzed for the expression of α-gal epitopes and the binding of anti-Gal, and vaccine efficacy was assessed in vitro and in vivo.ResultsEffective synthesis of α-gal epitopes was demonstrated after processing of PDAC tumor lysates from 10 different patients, and tumor lysates readily bound an anti-Gal monoclonal antibody. α-gal(+) PDAC tumor lysate vaccines elicited strong antibody production against multiple tumor-associated antigens and activated multiple tumor-specific T cells. The lysate vaccines stimulated a robust immune response in animal models, resulting in tumor suppression and a significant improvement in survival without any adverse events.ConclusionsOur data suggest that α-gal(+) PDAC tumor lysate vaccination may be a practical and effective new immunotherapeutic approach for treating pancreatic cancer.

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Sensitivity of Dendritic Cells to Microenvironment Signals

Cited by 34 publications

References 81 publications

Human adipose mesenchymal stem cells modulate myeloid cells toward an anti-inflammatory and reparative phenotype: role of IL-6 and PGE2

Human adipose mesenchymal stem cells modulate myeloid cells toward an anti-inflammatory and reparative phenotype: role of IL-6 and PGE2

HCC-Derived Exosomes: Critical Player and Target for Cancer Immune Escape

A practical approach to pancreatic cancer immunotherapy using resected tumor lysate vaccines processed to express α-gal epitopes

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