Toll-Like Receptor-Agonists in the Treatment of Skin Cancer: History, Current Developments and Future Prospects

Wenzel, Joerg; Tormo, Damià; Tüting, Thomas

doi:10.1007/978-3-540-72167-3_10

Cited by 13 publications

(6 citation statements)

References 92 publications

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“…However, we also show that IFN, per se , does not recapitulate the anti-melanoma activity of [pIC] PEI in cultured cells. Moreover, [pIC] PEI can display an efficient anti-melanoma activity in animals with defective NK, T or B cell signaling, a condition common of melanoma patients (Kirkwood et al, 2008; Wenzel et al, 2008). In addition to the xenografts in immunosuppressed and immunodeficient mice, our results in two additional in vivo models (MDA-5 deficient cells and autochthonous cutaneous melanomas generated in the Tyr::NRAS Q61K ; INK4a/ARF -/- mice), further emphasized the physiological relevance of our data.…”

Section: Discussionmentioning

confidence: 99%

“…Membrane-bound pattern recognition receptors of the Toll-Like Receptor family (particularly TLR-3, TLR-4, and TLR-7) can favor pathogen sequestration in autophagosomes (Delgado and Deretic, 2009; Levine and Deretic, 2007). These TLRs have a restricted expression pattern, being enriched in cells of the immune system, such as macrophages and dendritic cells (Paulos et al, 2007; Wenzel et al, 2008). Whether melanoma cells have other sensors of viral pathogens that can be engaged to induce autophagy and cell death is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Targeted Activation of Innate Immunity for Therapeutic Induction of Autophagy and Apoptosis in Melanoma Cells

et al. 2009

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Summary Inappropriate drug delivery, secondary toxicities and persistent chemo- and immuno-resistance have traditionally compromised treatment response in melanoma. Using cellular systems and genetically engineered mouse models, we show that melanoma cells retain an innate ability to recognize cytosolic dsRNA and mount persistent stress response programs able to block tumor growth, even in highly immunosuppressed backgrounds. The dsRNA mimic polyinosine-polycytidylic acid (pIC), coadministered with polyethyleneimine (PEI) as a carrier, was identified as an unanticipated inducer of autophagy downstream of an exacerbated endosomal maturation program. A concurrent activity of the dsRNA helicase MDA-5 driving the proapoptotic protein NOXA resulted in an efficient autodigestion of melanoma cells. These results reveal tractable links for therapeutic intervention among dsRNA helicases, endo/lysosomes and apoptotic factors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeted Activation of Innate Immunity for Therapeutic Induction of Autophagy and Apoptosis in Melanoma Cells

et al. 2009

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“…Melanoma is a malignant tumor of melanocytes which causes the majority of skin cancer-related deaths worldwide [58, 157, 158]. Exposure to UV radiation is the main risk factor for the disease [58, 157, 159].…”

Section: Tlrs In Dermatologic Diseasementioning

confidence: 99%

“…Exposure to UV radiation is the main risk factor for the disease [58, 157, 159]. Melanocytes have the ability to help tumor progression in melanoma by responding to hyaluronic acid fragments through TLR 4 by inducing MMP and cytokine production [59].…”

Section: Tlrs In Dermatologic Diseasementioning

confidence: 99%

Toll-Like Receptors: Role in Dermatological Disease

Hari

Flach

Shi

et al. 2010

Mediators of Inflammation

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Toll-like receptors (TLRs) are a class of conserved receptors that recognize pathogen-associated molecular patterns (PAMPs) present in microbes. In humans, at least ten TLRs have been identified, and their recognition targets range from bacterial endotoxins to lipopeptides, DNA, dsRNA, ssRNA, fungal products, and several host factors. Of dermatological interest, these receptors are expressed on several skin cells including keratinocytes, melanocytes, and Langerhans cells. TLRs are essential in identifying microbial products and are known to link the innate and adaptive immune systems. Over the years, there have been significant advances in our understanding of TLRs in skin inflammation, cutaneous malignancies, and defence mechanisms. In this paper, we will describe the association between TLRs and various skin pathologies and discuss proposed TLR therapeutics.

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“…[5][6][7] TLR ligands represent a promising class of immunotherapeutics or vaccine adjuvants with the potential to generate an effective antitumor immune response. 8 Recognition of TLR7 ligands by TLR7 leads to the overall activation and maturation of antigen-presenting cells, such as dendritic cells (DCs), and the secretion of proinflammatory cytokines and type I IFN. After recognition of TLR7 ligand, mature DCs are able to fully activate effector T cells and drive more potent immune responses.…”

Section: Introductionmentioning

confidence: 99%

The TLR7 agonists imiquimod and gardiquimod improve DC-based immunotherapy for melanoma in mice

Zhang

et al. 2010

Cell Mol Immunol

107

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Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors that are essential for host immune responses. TLR ligands represent a promising class of immunotherapeutics or vaccine adjuvants with the potential to generate an effective antitumor immune response. The TLR7/8 agonists have aroused interest because they not only activate antigen-presenting cells but also promote activation of T and natural killer (NK) cells. However, the exact mechanism by which stimulation of these TLRs promotes immune responses remains unclear, and different TLR7/8 agonists have been found to induce different responses. In this study, we demonstrate that both gardiquimod and imiquimod promote the proliferation of murine splenocytes, stimulate the activation of splenic T, NK and natural killer T (NKT) cells, increase the cytolytic activity of splenocytes against B16 and MCA-38 tumor cell lines, and enhance the expression of costimulatory molecules and IL-12 by macrophages and bone marrow-derived dendritic cells (DCs). In a murine model, both agonists improved the antitumor effects of tumor lysate-loaded DCs, resulting in delayed growth of subcutaneous B16 melanoma tumors and suppression of pulmonary metastasis. Further, we found that gardiquimod demonstrated more potent antitumor activity than imiquimod. These results suggest that TLR7/8 agonists may serve as potent innate and adaptive immune response modifiers in tumor therapy. More importantly, they can be used as vaccine adjuvants to potentiate the efficiency of DC-based tumor immunotherapy.

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Toll-Like Receptor-Agonists in the Treatment of Skin Cancer: History, Current Developments and Future Prospects

Cited by 13 publications

References 92 publications

Targeted Activation of Innate Immunity for Therapeutic Induction of Autophagy and Apoptosis in Melanoma Cells

Targeted Activation of Innate Immunity for Therapeutic Induction of Autophagy and Apoptosis in Melanoma Cells

Toll-Like Receptors: Role in Dermatological Disease

The TLR7 agonists imiquimod and gardiquimod improve DC-based immunotherapy for melanoma in mice

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