Impaired Toll-like receptor 7 and 9 signaling: from chronic viral infections to cancer

Hirsch, Ivan; Caux, Christophe; Hasan, Uzma; Bendriss‐Vermare, Nathalie; Olive, Daniel

doi:10.1016/j.it.2010.07.004

Cited by 96 publications

(104 citation statements)

References 82 publications

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“…These data are consistent with the specific alteration of TLR9 response previously reported by us (19,20) and others on both human tumor and immune cells (17,28). Although pDC hyporesponsiveness to TLR9 ligands might be explained by receptor downregulation (17,28), we showed that it is rather due to a specific interference of the tumor microenvironment, for instance via IRF7 downregulation (29). Tumor-induced TLR9 loss of function might represent an immunosubversion mechanism to avoid immune alert by putative endogenous ligands for TLR9 within the tumor microenvironment, such as described in autoimmune disorders (30)(31)(32).…”

Section: Discussionsupporting

confidence: 93%

“…First, we showed in vitro and in vivo that TApDC from NEU15WT tumors were specifically altered in their ability to respond to TLR9 but not TLR7 ligands. These data are consistent with the specific alteration of TLR9 response previously reported by us (19,20) and others on both human tumor and immune cells (17,28). Although pDC hyporesponsiveness to TLR9 ligands might be explained by receptor downregulation (17,28), we showed that it is rather due to a specific interference of the tumor microenvironment, for instance via IRF7 downregulation (29).…”

Section: Discussionsupporting

confidence: 92%

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Tumor Promotion by Intratumoral Plasmacytoid Dendritic Cells Is Reversed by TLR7 Ligand Treatment

et al. 2013

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Plasmacytoid dendritic cells (pDC) are key regulators of antiviral immunity. In previous studies, we reported that pDC-infiltrating human primary breast tumors represent an independent prognostic factor associated with poor outcome. To understand this negative impact of tumor-associated pDC (TApDC), we developed an orthotopic murine mammary tumor model that closely mimics the human pathology, including pDC and regulatory T cell (Treg) infiltration. We showed that TApDC are mostly immature and maintain their ability to internalize antigens in vivo and to activate CD4 þ T cells. Most importantly, TApDC were specifically altered for cytokine production in response to Toll-like receptor (TLR)-9 ligands in vitro while preserving unaltered response to TLR7 ligands (TLR7L). In vivo pDC depletion delayed tumor growth, showing that TApDC provide an immunesubversive environment, most likely through Treg activation, thus favoring tumor progression. However, in vivo intratumoral administration of TLR7L led to TApDC activation and displayed a potent curative effect. Depletion of pDC and type I IFN neutralization prevented TLR7L antitumoral effect. Our results establish a direct contribution of TApDC to primary breast tumor progression and rationalize the application of TLR7 ligands to restore TApDC activation in breast cancer. Cancer Res; 73(15); 4629-40. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Tumor Promotion by Intratumoral Plasmacytoid Dendritic Cells Is Reversed by TLR7 Ligand Treatment

et al. 2013

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“…Using synthetic ligands of TLR9, they concluded that HBV can block plasmacytoid dendritic cell stimulation. 24 Our results revealed that the expression of TLR9 and its molecular signaling were decreased in the PBMCs of Iranian CHB patients; hence, it seems that HBV may use the same mechanisms to suppress PBMCs to reduce expression of TLR9 and its downstream signaling molecules.…”

Section: Expression Levels Of Target Genesmentioning

confidence: 58%

“…The authors concluded that HBV used several escape mechanisms to down-regulate and inactivate TLR9 in both plasmacytoid dendritic cells and B lymphocytes. 23 Hirsch et al 24 also demonstrated that HBV can lead to decreased expression of TLR9 and interferon-a in plasmacytoid dendritic cells via interaction with the regulatory receptors of plasmacytoid dendritic cells. Using synthetic ligands of TLR9, they concluded that HBV can block plasmacytoid dendritic cell stimulation.…”

Section: Expression Levels Of Target Genesmentioning

confidence: 98%

Decreased Expressions of Toll-Like Receptor 9 and Its Signaling Molecules in Chronic Hepatitis B Virus–Infected Patients

Sajadi

Mirzaei

Hassanshahi

et al. 2013

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Toll-like receptors (TLRs) play crucial roles in immune responses, especially innate immunity, against viral infections. Toll-like receptor 9 recognizes intracellular viral double-strand DNA, which leads to the activation of nuclear factor B (NF-jB) through the myeloid differentiation primary response 88 (MYD88) pathway. Defects in the expression of TLR9 and its signaling molecules may cause attenuated immune responses against hepatitis B virus.Objective.-To determine expression levels of TLR9 messenger RNA along with MYD88, interleukin 1 receptor-associated kinase 1 (IRAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6), and NF-jB in the peripheral blood mononuclear cells obtained from chronic hepatitis B virus (CHB)-infected patients.Design.-In this study, 60 CHB patients and 60 healthy controls were recruited and the expression of TLR9 and its downstream signaling molecules was examined by realtime polymerase chain reaction techniques using b-actin as a housekeeping gene.Results.-Our results showed that expression of TLR9, MYD88, IRAK1, TRAF6, and NF-jB in peripheral blood mononuclear cells of CHB patients was significantly decreased in comparison with healthy controls.Conclusions.-According to our results, it appears that CHB patients are unable to appropriately express genes in the TLR9 pathway, which may impede immune responses against hepatitis B virus infection. These results suggest a mechanism that may partially explain the fact that immune responses are disrupted in CHB patients.

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“…The interaction between HPV and components of the tumor microenvironment could impair TLR9 signaling and downregulate TLR9 gene expression leading to the reduction of the innate immune responses during chronic viral infections. New therapeutic approaches based on TLR agonists have then been proposed (Hirsch et al, 2010;Ohlschlager et al, 2011;Domingos-Pereira et al, 2013). The same inequity has been shown in other cancer types.…”

Section: Figure 1 Hematoxylin and Eosin (He) Staining And Expressionmentioning

confidence: 89%

Expression of Toll-like Receptor 9 Increases with Progression of Cervical Neoplasia in Tunisian Women - A Comparative Analysis of Condyloma, Cervical Intraepithelial Neoplasia and Invasive Carcinoma

Fehri¹,

Ennaifer²,

Ardhaoui³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Impaired Toll-like receptor 7 and 9 signaling: from chronic viral infections to cancer

Cited by 96 publications

References 82 publications

Tumor Promotion by Intratumoral Plasmacytoid Dendritic Cells Is Reversed by TLR7 Ligand Treatment

Tumor Promotion by Intratumoral Plasmacytoid Dendritic Cells Is Reversed by TLR7 Ligand Treatment

Decreased Expressions of Toll-Like Receptor 9 and Its Signaling Molecules in Chronic Hepatitis B Virus–Infected Patients

Expression of Toll-like Receptor 9 Increases with Progression of Cervical Neoplasia in Tunisian Women - A Comparative Analysis of Condyloma, Cervical Intraepithelial Neoplasia and Invasive Carcinoma

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