The Dark Side of Dendritic Cells: Development and Exploitation of Tolerogenic Activity That Favor Tumor Outgrowth and Immune Escape

Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of a timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including an angiogenic switch, immune escape, cancer stem cells, extra cellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced-p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer, and discuss the implications of such approaches in cancer treatment.

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Faculty Opinions recommendation of Variable processing and cross-presentation of HIV by dendritic cells and macrophages shapes CTL immunodominance and immune escape.

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

10.3410/f.725391973.793506830 ◽

2015 ◽

Author(s):

Persephone Borrow ◽

Thomas Partridge

Keyword(s):

Dendritic Cells ◽

Immune Escape ◽

Cross Presentation ◽

Variable Processing

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Induction of Maturation and Cytokine Release of Human Dendritic Cells by Helicobacter pylori

Infection and Immunity ◽

10.1128/iai.72.8.4416-4423.2004 ◽

2004 ◽

Vol 72 (8) ◽

pp. 4416-4423 ◽

Cited By ~ 76

Author(s):

Katharina Kranzer ◽

Alexander Eckhardt ◽

Michael Aigner ◽

Gertrud Knoll ◽

Ludwig Deml ◽

...

Keyword(s):

Helicobacter Pylori ◽

Dendritic Cells ◽

Immune System ◽

Immune Escape ◽

Cell Surface Expression ◽

Cytokine Release ◽

Proinflammatory Response ◽

Ulcer Disease ◽

H Pylori ◽

Human Dendritic Cells

ABSTRACT Helicobacter pylori causes a persistent infection in the human stomach, which can result in chronic gastritis and peptic ulcer disease. Despite an intensive proinflammatory response, the immune system is not able to clear the organism. However, the immune escape mechanisms of this common bacterium are not well understood. We investigated the interaction between H. pylori and human dendritic cells. Dendritic cells (DCs) are potent antigen-presenting cells and important mediators between the innate and acquired immune system. Stimulation of DCs with different concentrations of H. pylori for 8, 24, 48, and 72 h resulted in dose-dependent interleukin-6 (IL-6), IL-8, IL-10 and IL-12 production. Lipopolysaccharide (LPS) from Escherichia coli, a known DC maturation agent, was used as a positive control. The cytokine release after stimulation with LPS was comparable to that induced by H. pylori except for IL-12. After LPS stimulation IL-12 was only moderately released compared to the large amounts of IL-12 induced by H. pylori. We further investigated the potential of H. pylori to induce maturation of DCs. Fluorescence-activated cell sorting analysis of cell surface expression of maturation marker molecules such as CD80, CD83, CD86, and HLA-DR revealed equal upregulation after stimulation with H. pylori or LPS. We found no significant differences between H. pylori seropositive and seronegative donors of DCs with regard to cytokine release and upregulation of surface molecules. These data clearly demonstrate that H. pylori induces a strong activation and maturation of human immature DCs.

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T Lymphocyte Inhibition by Tumor-Infiltrating Dendritic Cells Involves Ectonucleotidase CD39 but Not Arginase-1

BioMed Research International ◽

10.1155/2015/891236 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Malika Trad ◽

Alexandrine Gautheron ◽

Jennifer Fraszczak ◽

Darya Alizadeh ◽

Claire Larmonier ◽

...

Keyword(s):

Dendritic Cells ◽

T Lymphocyte ◽

Tumor Antigens ◽

Immune Escape ◽

Mouse Tumor ◽

Tumor Immune Escape ◽

Cell Responses ◽

Arginase 1 ◽

T Lymphocyte Proliferation ◽

Tumor Environment

T lymphocytes activated by dendritic cells (DC) which present tumor antigens play a key role in the antitumor immune response. However, in patients suffering from active cancer, DC are not efficient at initiating and supporting immune responses as they participate to T lymphocyte inhibition. DC in the tumor environment are functionally defective and exhibit a characteristic of immature phenotype, different to that of DC present in nonpathological conditions. The mechanistic bases underlying DC dysfunction in cancer responsible for the modulation of T-cell responses and tumor immune escape are still being investigated. Using two different mouse tumor models, we showed that tumor-infiltrating DC (TIDC) are constitutively immunosuppressive, exhibit a semimature phenotype, and impair responder T lymphocyte proliferation and activation by a mechanism involving CD39 ectoenzyme.

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Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

Cells ◽

10.3390/cells9010161 ◽

2020 ◽

Vol 9 (1) ◽

pp. 161 ◽

Cited By ~ 5

Author(s):

Lonneke V. Nouwen ◽

Bart Everts

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Amino Acid ◽

Immune Responses ◽

Metabolic Pathways ◽

Immune Escape ◽

Mammalian Target Of Rapamycin ◽

Metabolic Reprogramming ◽

First Line

Myeloid cells, including macrophages and dendritic cells, represent an important first line of defense against infections. Upon recognition of pathogens, these cells undergo a metabolic reprogramming that supports their activation and ability to respond to the invading pathogens. An important metabolic regulator of these cells is mammalian target of rapamycin (mTOR). During infection, pathogens use host metabolic pathways to scavenge host nutrients, as well as target metabolic pathways for subversion of the host immune response that together facilitate pathogen survival. Given the pivotal role of mTOR in controlling metabolism and DC and macrophage function, pathogens have evolved strategies to target this pathway to manipulate these cells. This review seeks to discuss the most recent insights into how pathogens target DC and macrophage metabolism to subvert potential deleterious immune responses against them, by focusing on the metabolic pathways that are known to regulate and to be regulated by mTOR signaling including amino acid, lipid and carbohydrate metabolism, and autophagy.

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Type 1 conventional dendritic cells are systemically dysregulated early in pancreatic carcinogenesis

Journal of Experimental Medicine ◽

10.1084/jem.20190673 ◽

2020 ◽

Vol 217 (8) ◽

Cited By ~ 10

Author(s):

Jeffrey H. Lin ◽

Austin P. Huffman ◽

Max M. Wattenberg ◽

David M. Walter ◽

Erica L. Carpenter ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Intraepithelial Neoplasia ◽

Underlying Mechanism ◽

T Cell Response ◽

Pancreatic Carcinogenesis ◽

Tumor Outgrowth ◽

Systemic Onset

Type 1 conventional dendritic cells (cDC1s) are typically thought to be dysregulated secondarily to invasive cancer. Here, we report that cDC1 dysfunction instead develops in the earliest stages of preinvasive pancreatic intraepithelial neoplasia (PanIN) in the KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-Cre–driven (KPC) mouse model of pancreatic cancer. cDC1 dysfunction is systemic and progressive, driven by increased apoptosis, and results in suboptimal up-regulation of T cell–polarizing cytokines during cDC1 maturation. The underlying mechanism is linked to elevated IL-6 concomitant with neoplasia. Neutralization of IL-6 in vivo ameliorates cDC1 apoptosis, rescuing cDC1 abundance in tumor-bearing mice. CD8+ T cell response to vaccination is impaired as a result of cDC1 dysregulation. Yet, combination therapy with CD40 agonist and Flt3 ligand restores cDC1 abundance to normal levels, decreases cDC1 apoptosis, and repairs cDC1 maturation to drive superior control of tumor outgrowth. Our study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation during pancreatic carcinogenesis and suggests therapeutically tractable strategies toward cDC1 repair.

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