IFNβ Produced by TLR4-Activated Tumor Cells Is Involved in Improving the Antitumoral Immune Response

Núñez, Nicolás Gonzalo; Andreani, Virginia; Crespo, María Inés; Nocera, David Andrés; Breser, María Laura; Morón, Gabriel; Dejager, Lien; Libert, Claude; Rivero, Virginia; Maccioni, Mariana

doi:10.1158/0008-5472.can-11-0534

Cited by 45 publications

(28 citation statements)

References 46 publications

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“…In murine melanoma cells, TLR4 activation before inoculation significantly inhibits in vivo tumor growth through T cell activation (Andreani et al 2007;Nunez et al 2012). By contrast, other studies suggest that TLR activation induces tumor cell proliferation and promotes angiogenesis, invasion, and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Signaling Promotes the Migration of Human Melanoma Cells

Takazawa

Kiniwa

Ogawa

et al. 2014

Tohoku J. Exp. Med.

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Immune cell Toll-like receptors (TLRs) recognize conserved microbial components, leading to immune and inflammatory responses. However, TLRs are also expressed in cancer cells, including melanoma cells, which express TLR2-4. TLR4 ligands have received attention as immunotherapies; therefore, we assessed the expression of TLR4 in human melanoma specimens (29 primary lesions and 28 metastatic lesions) representing different types of melanoma. A high percentage (≥ 90%) of melanoma lesions expressed TLR4, as judged by immunohistochemistry. Next, the role of TLR4 in cell proliferation and migration was assessed using the TLR4-positive (TLR4 + ) melanoma cell lines 501mel and 888mel, and TLR4-negative (TLR4 -) 928mel melanoma cells. Lipopolysaccharide (LPS), a TLR4 agonist, increased the proliferation of TLR4 + melanoma cells but not of TLR4 -928mel cells. The proliferation-inducing effect of LPS in 888mel cells was abolished by blockade of TLR4 signaling via treatment with short interfering RNA (siRNA) targeting TLR4 or myeloid differentiation primary response gene 88 (MyD88), a molecule downstream of TLR4. However, knockdown of TLR4 or MyD88 expression did not affect the LPS-induced proliferation of 501mel cells, suggesting that residual TLR4 signaling is sufficient to maintain cell proliferation. By contrast, LPS increased the migration of TLR4 + melanoma cells, and this effect was substantially inhibited by TLR4 or MyD88 knockdown. Furthermore, TLR4 knockdown decreased cell migration even in the absence of LPS, suggesting the presence of an endogenous TLR4 ligand(s) in melanoma cells. TLR4 signaling may contribute to melanoma progression, and caution should be exercised when using TLR4 ligands as adjuvant therapy for cancer.

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Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Signaling Promotes the Migration of Human Melanoma Cells

Takazawa

Kiniwa

Ogawa

et al. 2014

Tohoku J. Exp. Med.

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“…The ligation of CD40 on the surface of tumor cells inhibits the growth of tumor and induces apoptosis [46]. Besides CD40LG, IFN-β has also been found to play critical role in anti-tumoral immune response [47]. Interestingly, Moschonas has indicated that stimulation of CD40 by its ligand has promoted the expression of IFN-β through the binding IRF7 to its promoter.…”

Section: Discussionmentioning

confidence: 99%

Global transcriptome-wide analysis of CIK cells identify distinct roles of IL-2 and IL-15 in acquisition of cytotoxic capacity against tumor

et al. 2014

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BackgroundCytokine-induced killer (CIK) cells are an emerging approach of cancer treatment. Our previous study have shown that CIK cells stimulated with combination of IL-2 and IL-15 displayed improved proliferation capacity and tumor cytotoxicity. However, the mechanisms of CIK cell proliferation and acquisition of cytolytic function against tumor induced by IL-2 and IL-15 have not been well elucidated yet.MethodsCIKIL-2 and CIKIL-15 were generated from peripheral blood mononuclear cells primed with IFN-γ, and stimulated with IL-2 and IL-15 in combination with OKT3 respectively. RNA-seq was performed to identify differentially expressed genes, and gene ontology and pathways based analysis were used to identify the distinct roles of IL-2 and IL-15 in CIK preparation.ResultsThe results indicated that CIKIL-15 showed improved cell proliferation capacity compared to CIKIL-2. However, CIKIL-2 has exhibited greater tumor cytotoxic effect than CIKIL-15. Employing deep sequencing, we sequenced mRNA transcripts in CIKIL-2 and CIKIL-15. A total of 374 differentially expressed genes (DEGs) were identified including 175 up-regulated genes in CIKIL-15 and 199 up-regulated genes in CIKIL-2. Among DEGs in CIKIL-15, Wnt signaling and cell adhesion were significant GO terms and pathways which related with their functions. In CIKIL-2, type I interferon signaling and cytokine-cytokine receptor interaction were significant GO terms and pathways. We found that the up-regulation of Wnt 4 and PDGFD may contribute to enhanced cell proliferation capacity of CIKIL-15, while inhibitory signal from interaction between CTLA4 and CD80 may be responsible for the weak proliferation capacity of CIKIL-2. Moreover, up-regulated expressions of CD40LG and IRF7 may make for improved tumor cytolytic function of CIKIL-2 through type I interferon signaling.ConclusionsThrough our findings, we have preliminarily elucidated the cells proliferation and acquisition of tumor cytotoxicity mechanism of CIKIL-15 and CIKIL-2. Better understanding of these mechanisms will help to generate novel CIK cells with greater proliferation potential and improved tumor cytolytic function.

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“…Thus, both CD40L and IFN-b confer negative effects on carcinoma growth by improving tumor cell immunogenicity (4,14,15) and triggering direct antiproliferative and proapoptotic properties (37)(38)(39)(40)(41). Both CD40L and type I IFNs also act on immune cells to augment Th1 cell responses, enhance expression of MHC class I molecules, and generate NK and T cellmediated cytotoxicity (reviewed in Refs.…”

Section: Discussionmentioning

confidence: 99%

CD40 Stimulates a “Feed-Forward” NF-κB–Driven Molecular Pathway That Regulates IFN-β Expression in Carcinoma Cells

Moschonas

Ioannou

Eliopoulos

2012

The Journal of Immunology

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IFN-β and the CD40L (CD154) share important roles in the antiviral and antitumor immune responses. In this study, we show that CD40 receptor occupancy results in IFN-β upregulation through an unconventional “feed-forward” mechanism, which is orchestrated by canonical NF-κB and involves the sequential de novo synthesis of IFN regulatory factor (IRF)1 and Viperin (RSAD2), an IRF1 target. RelA (p65) NF-κB, IRF1, and Viperin-dependent IRF7 binding to the IFN-β promoter largely controls its activity. However, full activation of IFN-β also requires the parallel engagement of noncanonical NF-κB2 signaling leading to p52 recruitment to the IFN-β promoter. These data define a novel link between CD40 signaling and IFN-β expression and provide a telling example of how signal propagation can be exploited to ensure efficient regulation of gene expression.

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IFNβ Produced by TLR4-Activated Tumor Cells Is Involved in Improving the Antitumoral Immune Response

Cited by 45 publications

References 46 publications

Toll-Like Receptor 4 Signaling Promotes the Migration of Human Melanoma Cells

Toll-Like Receptor 4 Signaling Promotes the Migration of Human Melanoma Cells

Global transcriptome-wide analysis of CIK cells identify distinct roles of IL-2 and IL-15 in acquisition of cytotoxic capacity against tumor

CD40 Stimulates a “Feed-Forward” NF-κB–Driven Molecular Pathway That Regulates IFN-β Expression in Carcinoma Cells

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