Plasmacytoid dendritic cells regulate colitis-associated tumorigenesis by controlling myeloid-derived suppressor cell infiltration

Hong, Eock Kee; Cho, Jaewon; Ahn, Jae-Hee; Kwon, Bo-Eun; Kweon, Mi‐Na; Seo, Sang‐Uk; Yoon, Byung–Il; Chang, Shau‐Jin; Ko, Hyun‐Jeong

doi:10.1016/j.canlet.2020.08.007

Cited by 13 publications

(13 citation statements)

References 56 publications

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“…Cleared tumor pieces were digested using an enzyme mixture containing 0.5 mg/mL Collagenase D (Cat#11088866001, Roche Dagnostics GmBH, Mannheim, Germany) and 0.02 mg/mL DNase I (Cat#10104159001, Sigma Aldrich, St. Louis, MO, USA) in RPMI 1640 at 37 °C for 45 min and passed through 70 μM cell strainers (BD Biosciences, Franklin Lakes, NJ, USA). A Percoll gradient (Cat#17-0891-01, GE Healthcare, Chicago, IL, USA) was then used to separate cancer cells and enrich lymphocytes as described previously [ 16 ].…”

Section: Methodsmentioning

confidence: 99%

AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway

et al. 2021

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Background AMP-activated protein kinase (AMPK) is a metabolic sensor that maintains energy homeostasis. AMPK functions as a tumor suppressor in different cancers; however, its role in regulating antitumor immunity, particularly the function of regulatory T cells (Tregs), is poorly defined. Methods AMPKα1fl/flFoxp3YFP-Cre, Foxp3YFP-Cre, Rag1−/−, and C57BL/6 J mice were used for our research. Flow cytometry and cell sorting, western blotting, immuno-precipitation, immuno-fluorescence, glycolysis assay, and qRT-PCR were used to investigate the role of AMPK in suppressing programmed cell death 1 (PD-1) expression and for mechanistic investigation. Results The deletion of the AMPKα1 subunit in Tregs accelerates tumor growth by increasing the expression of PD-1. Metabolically, loss of AMPK in Tregs promotes glycolysis and the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme of the mevalonate pathway. Mechanistically, AMPK activates the p38 mitogen-activated protein kinase (MAPK) that phosphorylates glycogen synthase kinase-3β (GSK-3β), inhibiting the expression of PD-1 in Tregs. Conclusion Our study identified an AMPK regulatory mechanism of PD-1 expression via the HMGCR/p38 MAPK/GSK3β signaling pathway. We propose that the AMPK activator can display synergic antitumor effect in murine tumor models, supporting their potential clinical use when combined with anti-PD-1 antibody, anti-CTLA-4 antibody, or a HMGCR inhibitor.

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Section: Methodsmentioning

confidence: 99%

AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway

et al. 2021

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“…− Notch-2-DCs with less migration to MLNs and antigen presentation capacity to CD8 + T cells [156]. − Plasmacytoid dendritic cells (pDCs) induce recruitment of MDSCs into intestinal mucosa in a CAC mouse model [157].…”

Section: Dendritic Cells (Dcs)mentioning

confidence: 99%

“…This may therefore impact immunosurveillance and favor the dysplasia to carcinoma progression in mice [ 156 ]. Interestingly, pDCs could also play a role in the development of IBD-associated cancer through the recruitment of MDSCs, as observed in a mouse model for CAC [ 157 ] ( Table 1 ). These MDSCs are known for their suppressor capacity, are increased in several malignancies and have been implicated in tumorigenesis [ 186 , 187 ].…”

Section: The Role Of the Immune System In Ibd-associated Cancermentioning

confidence: 99%

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The Role of the Immune System in IBD-Associated Colorectal Cancer: From Pro to Anti-Tumorigenic Mechanisms

Frigerio

Lartey

D’Haens

et al. 2021

IJMS

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Patients with inflammatory bowel disease (IBD) have increased incidence of colorectal cancer (CRC). IBD-associated cancer follows a well-characterized sequence of intestinal epithelial changes, in which genetic mutations and molecular aberrations play a key role. IBD-associated cancer develops against a background of chronic inflammation and pro-inflammatory immune cells, and their products contribute to cancer development and progression. In recent years, the effect of the immunosuppressive microenvironment in cancer development and progression has gained more attention, mainly because of the unprecedented anti-tumor effects of immune checkpoint inhibitors in selected groups of patients. Even though IBD-associated cancer develops in the background of chronic inflammation which is associated with activation of endogenous anti-inflammatory or suppressive mechanisms, the potential role of an immunosuppressive microenvironment in these cancers is largely unknown. In this review, we outline the role of the immune system in promoting cancer development in chronic inflammatory diseases such as IBD, with a specific focus on the anti-inflammatory mechanisms and suppressive immune cells that may play a role in IBD-associated tumorigenesis.

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“…For example, it has been reported that the expression of TLR2 gradually increased from normal mucosa, to Helicobacter pylori -gastritis, to metaplasia, to dysplasia [ 19 ]. Hong et al [ 20 ] have demonstrated the role of TLR3/7-mediated signaling in the induction of CAC using a well-established murine model of azoxymethane (AOM)/dextran sulfate sodium (DSS) treatment. The role of TLR7 and TLR8 expression and signaling in chronic pancreatitis-linked pancreatic carcinogenesis has also been determined [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

TLR4 signaling in the development of colitis-associated cancer and its possible interplay with microRNA-155

2021

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Ulcerative colitis (UC) has closely been associated with an increased risk of colorectal cancer. However, the exact mechanisms underlying colitis-associated cancer (CAC) development remain unclear. As a classic pattern-recognition receptor, Toll like receptor (TLR)4 is a canonical receptor for lipopolysaccharide of Gram-negative bacteria (including two CAC-associated pathogens Fusobacterium nucleatum and Salmonella), and functions as a key bridge molecule linking oncogenic infection to colonic inflammatory and malignant processes. Accumulating studies verified the overexpression of TLR4 in colitis and CAC, and the over-expressed TLR4 might promote colitis-associated tumorigenesis via facilitating cell proliferation, protecting malignant cells against apoptosis, accelerating invasion and metastasis, as well as contributing to the creation of tumor-favouring cellular microenvironment. In recent years, considerable attention has been focused on the regulation of TLR4 signaling in the context of colitis-associated tumorigenesis. MicroRNA (miR)-155 and TLR4 exhibited a similar dynamic expression change during CAC development and shared similar CAC-promoting properties. The available data demonstrated an interplay between TLR4 and miR-155 in the context of different disorders or cell lines. miR-155 could augment TLR4 signaling through targeting negative regulators SOCS1 and SHIP1; and TLR4 activation would induce miR-155 expression via transcriptional and post-transcriptional mechanisms. This possible TLR4-miR-155 positive feedback loop might result in the synergistic accelerating effect of TLR4 and miR-155 on CAC development.

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Plasmacytoid dendritic cells regulate colitis-associated tumorigenesis by controlling myeloid-derived suppressor cell infiltration

Cited by 13 publications

References 56 publications

AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway

AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway

The Role of the Immune System in IBD-Associated Colorectal Cancer: From Pro to Anti-Tumorigenic Mechanisms

TLR4 signaling in the development of colitis-associated cancer and its possible interplay with microRNA-155

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