NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma

BackgroundMacrophages and dendritic cells lacking the transcription factor nuclear factor kappa B p50 are skewed toward a proinflammatory phenotype, with increased cytokine expression and enhanced T cell activation; additionally, murine melanoma, fibrosarcoma, colon carcinoma, and glioblastoma grow slower in p50−/−mice. We therefore evaluated the efficacy of p50-negative immature myeloid cells (p50-IMCs) adoptively transferred into tumor-bearing hosts. Immature cells were used to maximize tumor localization, and pretreatment with 5-fluorouracil (5FU) was examined due to its potential to impair marrow production of myeloid cells, to target tumor myeloid cells and to release tumor neoantigens.MethodsWild-type (WT)-IMC or p50-IMC were generated by culturing lineage-negative marrow cells from WT or p50−/−mice in media containing thrombopoietin, stem cell factor and Flt3 ligand for 6 days followed by monocyte colony-stimulating factor for 1 day on ultralow attachment plates. Mice inoculated with Hi-Myc prostate cancer (PCa) cells or K-RasG12Dpancreatic ductal carcinoma (PDC)-luciferase cells received 5FU followed 5 days later by three doses of 107immature myeloid cells (IMC) every 3–4 days.ResultsPCa cells grew slower in p50−/−mice, and absence of host p50 prolonged the survival of mice inoculated orthotopically with PDC cells. IMC from Cytomegalovirus (CMV)-luciferase mice localized to tumor, nodes, spleen, marrow, and lung. 5FU followed by p50-IMC slowed PCa and PDC tumor growth, ~3-fold on average, in contrast to 5FU followed by WT-IMC, 5FU alone or p50-IMC alone. Slowed tumor growth was evident for 93% of PCa but only 53% of PDC tumors; we therefore focused on PCa for additional IMC analyses. In PCa, p50-IMC matured into F4/80+macrophages, as well as CD11b+F4/80−CD11c+conventional dendritic cells (cDCs). In both tumor and draining lymph nodes, p50-IMC generated more macrophages and cDCs than WT-IMC. Activated tumor CD8+T cells were increased fivefold by p50-IMC compared with WT-IMC, and antibody-mediated CD8+T cell depletion obviated slower tumor growth induced by 5FU followed by p50-IMC.Conclusions5FU followed by p50-IMC slows the growth of murine prostate and pancreatic carcinoma and depends on CD8+T cell activation. Deletion of p50 in patient-derived marrow CD34+cells and subsequent production of IMC for adoptive transfer may contribute to the therapy of these and additional cancers.

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Faculty Opinions recommendation of The brain as an immune privileged site: dendritic cells of the central nervous system inhibit T cell activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1014090.200835 ◽

2003 ◽

Author(s):

Magdalena Plebanski

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

The Central Nervous System ◽

The Brain ◽

Privileged Site

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Faculty Opinions recommendation of Listeria-infected myeloid dendritic cells produce IFN-beta, priming T cell activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1026752.325366 ◽

2005 ◽

Author(s):

Charles Czuprynski

Keyword(s):

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Myeloid Dendritic Cells

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Faculty Opinions recommendation of Mast cells and dendritic cells form synapses that facilitate antigen transfer for T cell activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725742980.793509477 ◽

2015 ◽

Author(s):

Vivian Tang

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Mast Cells ◽

T Cell Activation ◽

Cell Activation ◽

Antigen Transfer

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CD14 Expressing Precursors Give Rise to Highly Functional Conventional Dendritic Cells for Use as Dendritic Cell Vaccine

Cancers ◽

10.3390/cancers13153818 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3818

Author(s):

Maud Plantinga ◽

Denise A. M. H. van den Beemt ◽

Ester Dünnebach ◽

Stefan Nierkens

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Cord Blood ◽

T Cell Activation ◽

Cell Activation ◽

Ex Vivo ◽

Dendritic Cell Vaccine ◽

Cell Vaccine ◽

Activated T Cells

Induction of long-lasting immunity by dendritic cells (DCs) makes them attractive candidates for anti-tumor vaccination. Although DC vaccinations are generally considered safe, clinical responses remain inconsistent in clinical trials. This initiated studies to identify subsets of DCs with superior capabilities to induce effective and memory anti-tumor responses. The use of primary DCs has been suggested to overcome the functional limitations of ex vivo monocyte-derived DCs (moDC). The ontogeny of primary DCs has recently been revised by the introduction of DC3, which phenotypically resembles conventional (c)DC2 as well as moDC. Previously, we developed a protocol to generate cDC2s from cord blood (CB)-derived stem cells via a CD115-expressing precursor. Here, we performed index sorting and single-cell RNA-sequencing to define the heterogeneity of in vitro developed DC precursors and identified CD14+CD115+ expressing cells that develop into CD1c++DCs and the remainder cells brought about CD123+DCs, as well as assessed their potency. The maturation status and T-cell activation potential were assessed using flow cytometry. CD123+DCs were specifically prone to take up antigens but only modestly activated T-cells. In contrast, CD1c++ are highly mature and specialized in both naïve as well as antigen-experienced T-cell activation. These findings show in vitro functional diversity between cord blood stem cell-derived CD123+DC and CD1c++DCs and may advance the efficiency of DC-based vaccines.

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DCision-making in tumors governs T cell anti-tumor immunity

Oncogene ◽

10.1038/s41388-021-01946-8 ◽

2021 ◽

Author(s):

Francesca Alfei ◽

Ping-Chih Ho ◽

Wan-Lin Lo

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Dendritic Cell ◽

Cancer Treatment ◽

Tumor Immunity ◽

T Cell Activation ◽

Cell Activation ◽

Genetic Alterations ◽

Immune Checkpoint Blockade ◽

Oncological Treatment

AbstractThe exploitation of T cell-based immunotherapies and immune checkpoint blockade for cancer treatment has dramatically shifted oncological treatment paradigms and broadened the horizons of cancer immunology. Dendritic cells have emerged as the critical tailors of T cell immune responses, which initiate and coordinate anti-tumor immunity. Importantly, genetic alterations in cancer cells, cytokines and chemokines produced by cancer and stromal cells, and the process of tumor microenvironmental regulation can compromise dendritic cell–T cell cross-talk, thereby disrupting anti-tumor T cell responses. This review summarizes how T cell activation is controlled by dendritic cells and how the tumor microenvironment alters dendritic cell properties in the context of the anti-tumor immune cycle. Furthermore, we will highlight therapeutic options for tailoring dendritic cell-mediated decision-making in T cells for cancer treatment.

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Response of the Splenic Dendritic Cell Population to Malaria Infection

Infection and Immunity ◽

10.1128/iai.72.7.4233-4239.2004 ◽

2004 ◽

Vol 72 (7) ◽

pp. 4233-4239 ◽

Cited By ~ 53

Author(s):

Andrew L. Leisewitz ◽

Kirk A. Rockett ◽

Bonginkosi Gumede ◽

Margaret Jones ◽

Britta Urban ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Dendritic Cell ◽

Cell Population ◽

T Cell Activation ◽

Malaria Infection ◽

Cell Activation ◽

Splenic Dendritic Cell ◽

Dendritic Cell Population

ABSTRACT Dendritic cells, particularly those residing in the spleen, are thought to orchestrate acquired immunity to malaria, but it is not known how the splenic dendritic cell population responds to malaria infection and how this response compares with the responses of other antigen-presenting cells. We investigated this question for Plasmodium chabaudi AS infection in C57BL/6 mice. We found that dendritic cells, defined here by the CD11c marker, migrated from the marginal zone of the spleen into the CD4+ T-cell area within 5 days after parasites entered the bloodstream. This contrasted with the results observed for the macrophage and B-cell populations, which expanded greatly but did not show any comparable migration. Over the same time period dendritic cells showed upregulation of CD40, CD54, and CD86 costimulatory molecules that are required for successful T-cell activation. In dendritic cells, the peak intracellular gamma interferon expression (as shown by fluorescence-activated cell sorting) was on day 5, 2 days earlier than the peak expression in B-cells or macrophages. These findings show that splenic dendritic cells are actively engaged in the earliest phase of malarial infection in vivo and are likely to be critical in shaping the subsequent immune response.

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Abstract 13287: Dendritic Cells Play a Critical Role in the Initiation of Atherosclerosis

Circulation ◽

10.1161/circ.130.suppl_2.13287 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Mengyao Jin ◽

Peng Liu

Keyword(s):

Cell Proliferation ◽

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Critical Role ◽

Cell Interaction ◽

Plaque Formation ◽

T Cell Proliferation ◽

Control Group

Introduction: Dendritic cells (DCs) that are known as professional antigen-presenting cells have been found to pre-locate in non-inflammatory arterial wall and increasingly accumulate during atherosclerosis progression. Previous findings suggested that residential DCs in the intima are responsible for capturing modified lipids and forming foam cells during the initiation of atherosclerosis. Hypothesis: DC accumulation and enhanced DC-T cell interaction play a critical role in the initiation of atherosclerosis. Methods: We measured plaque formation, vascular DC accumulation and antigen-specific T cell proliferation mediated by isolated aortic cells in ApoE-/- mice, as well as DTR-CD11c/ApoE-/- or DTR-CD11b/ApoE-/- mice for conditional depletion of DCs or macrophages, respectively. A brief high-fat diet for 10 days was used as a model of initial atherosclerosis. Results: In addition to increased intimal DC accumulation and plaque formation in aortic roots, 10 days of HFD induced T cell infiltration in ApoE-/- mice, compared to those without HFD as the control. Isolated aortic cells from mice with 10-day HFD showed stronger capability in inducing antigen-specific T cell proliferation, compare to the control (HFD: 3.14±0.71%; no HFD: 1.56±0.36%; p=0.022). Single diphtheria toxin (DT) injection at day 1 yielded approximately 50% decrease in intimal DC accumulation, as well as 60% attenuation in plaque formation in DTR-CD11c/ApoE-/- mice after 10-day HFD. Capability of stimulating antigen-specific T cell proliferation was also impaired in aortic cells from DC-depleted mice (DT-treated: 1.62±0.30%; PBS-treated: 3.04±0.59%; p= 0.004), along with reduction in indirect conduction of T cell activation. In contrast, no significant changes were found in plaque formation and DC accumulation in DT-injected DTR-CD11b/ApoE-/- mice after 10 days of HFD, compared to control group. Furthermore, depletion of CD11b+ macrophages in either aortas or spleens didn’t alter capability of inducing antigen-specific T cell proliferation in DT-injected mice. Conclusions: These results suggested that vascular DCs rather than macrophages play a more important role in T cell activation and initiation of atherosclerosis.

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Immunomodulatory Effects of Polysaccharide from Marine FungusPhoma herbarumYS4108 on T Cells and Dendritic Cells

Mediators of Inflammation ◽

10.1155/2014/738631 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Song Chen ◽

Ran Ding ◽

Yan Zhou ◽

Xian Zhang ◽

Rui Zhu ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Molecular Mechanisms ◽

Interleukin 12 ◽

Related Factors ◽

Knock Out ◽

Specific Immunity

YCP, as a kind of natural polysaccharides from the mycelium of marine filamentous fungusPhoma herbarumYS4108, has great antitumor potentialviaenhancement of host immune response, but little is known about the molecular mechanisms. In the present study, we mainly focused on the effects and mechanisms of YCP on the specific immunity mediated by dendritic cells (DCs) and T cells. T cell /DC activation-related factors including interferon- (IFN-)γ, interleukin-12 (IL-12), and IL-4 were examined with ELISA. Receptor knock-out mice and fluorescence-activated cell sorting are used to analyze the YCP-binding receptor of T cells and DCs. RT-PCR is utilized to measure MAGE-A3 for analyzing the tumor-specific killing effect. In our study, we demonstrated YCP can provide the second signal for T cell activation, proliferation, and IFN-γproduction through binding to toll-like receptor- (TLR-) 2 and TLR-4. YCP could effectively promote IL-12 secretion and expression of markers (CD80, CD86, and MHC II)viaTLR-4 on DCs. Antigen-specific immunity against mouse melanoma cells was strengthened through the activation of T cells and the enhancement of capacity of DCs by YCP. The data supported that YCP can exhibit specific immunomodulatory capacity mediated by T cells and DCs.

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