Disease-Independent Skin Recruitment and Activation of Plasmacytoid Predendritic Cells Following Imiquimod Treatment

Urosevic, Mirjana; Dummer, Reinhard; Conrad, Curdin; Beyeler, Mirjam; Laine, Elisabeth; Burg, Günter; Gilliet, Michel

doi:10.1093/jnci/dji207

Cited by 171 publications

(161 citation statements)

References 53 publications

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“…Topical application of Aldara, a cream containing 5% of the TLR7-agonist IMQ, is an effective treatment for BCC and AK, and its major mode of action is thought to be TLR7 dependent. Indeed, topical application of Aldara results in increased infiltration of pDCs, a cell type that expresses high levels of TLR7 and is the main producer of type I interferon (IFN) 6 . Furthermore, Aldara induces local psoriasis-like symptoms in susceptible humans and in mice, such as inflammation, thickening and scaling of the skin [20][21][22] .…”

Section: Resultsmentioning

confidence: 99%

“…pDCs have been reported as the most prominent cell type infiltrating BCC following Aldara treatment 6 and as crucial for Aldara-dependent anti-tumour effects in murine melanoma 7 . To investigate whether this is also the case in human AK, we stained four AK sections with CD123, a marker for human pDCs.…”

Section: Aldara Induces Keratinocyte Proliferation In Human Nmscmentioning

confidence: 99%

“…Observations in BCC and AK patients suggest that recruitment of plasmacytoid dendritic cells (pDCs) into the malignant tissue is responsible for the therapeutic effect [4][5][6] . Recently, it was shown that Aldara treatment resulted in pDC-mediated tumour killing in a murine melanoma model 7 .…”

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confidence: 99%

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Aldara activates TLR7-independent immune defence

et al. 2013

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Aldara is a cream used for topical treatment of non-melanoma skin cancer, and is thought to act through stimulation of anti-tumour immunity. The active ingredient, imiquimod, has been shown to stimulate toll-like receptor 7. Aldara also induces psoriasis-like lesions when applied to naive murine skin, and as such is used as a mouse model for psoriasis. Here we find that in naive murine skin, Aldara induces inflammation largely independently of toll-like receptor 7. Surprisingly, inflammasome activation, keratinocyte death and interleukin 1 release also occur in response to the vehicle cream in the absence of imiquimod. We show that isostearic acid, a major component of the vehicle, promotes inflammasome activation in cultured keratinocytes, and so may contribute to the observed effects of Aldara on murine skin. Aldara therefore stimulates at least two immune pathways independently, and both imiquimod and vehicle are required for a full inflammatory response. Although it remains to be tested, it is possible that imiquimod-independent effects also contribute to the therapeutic efficacy of Aldara.

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Section: Resultsmentioning

confidence: 99%

Section: Aldara Induces Keratinocyte Proliferation In Human Nmscmentioning

confidence: 99%

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Aldara activates TLR7-independent immune defence

et al. 2013

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“…The known functions of these mediators explain, at least in part, many cellular responses to imiquimod including activation and application-site-directed migration of dendritic cells and their precursors as well as attraction and stimulation of cytotoxic T-lymphocytes and other immune cells. Along this line, it has been demonstrated that plasmacytoid dendritic cells accumulate in subcutaneous melanoma metastases in a mouse model (Palamara et al, 2004) and that plasmacytoid predendritic cells migrate into the skin (Urosevic et al, 2005) following application of imiquimod. The net result of the imiquimod-induced cytokine production is a Th1-weighted cellular immune response, while Th2 signaling pathways appear to be suppressed.…”

Section: Tlr7 and Tlr8 As Targets In Cancer Therapymentioning

confidence: 98%

TLR7 and TLR8 as targets in cancer therapy

2008

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Small-molecule agonists at Toll-like receptor 7 (TLR7) and TLR8 have sparked a vivid interest in cancer research owing to their profound antitumoral activity. The lead compound of the imidazoquinoline family, imiquimod, is marketed as a topical formulation. It is efficacious against many primary skin tumors and cutaneous metastases. Using different imidazoquinoline species, distinct functions of TLR7 and TLR8 have been discovered. The predominant antitumoral mode of action of these agents is TLR7/ 8-mediated activation of the central transcription factor nuclear factor-jB, which leads to induction of proinflammatory cytokines and other mediators. Cutaneous dendritic cells are the primary responsive cell type and initiate a strong Th1-weighted antitumoral cellular immune response. Recent research has shown that dendritic cells themselves acquire direct antitumoral activity upon stimulation by imiquimod. In addition, there are a number of secondary effects on the molecular and cellular level that can be explained through the activation of TLR7/8. The proinflammatory activity of imiquimod, but not resiquimod, appears to be augmented by suppression of a regulatory mechanism, which normally limits inflammatory responses. This is achieved independently of TLR7/8 through interference with adenosine receptor signaling pathways. Finally, at higher concentrations imiquimod exerts Bcl-2-and caspase-dependent proapoptotic activity against tumor cells.

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“…Oligodeoxynucleotides (ODN) with unmethylated deoxycytidyldeoxyguanosine (CpG) dinucleotides (CpG ODN) mimic the immunostimulatory activity of bacterial DNA recognised by the Toll-like receptor 9 (TLR9) and are potent adjuvants utilised in cancer therapy (Jahrsdorfer et al, 2005). Imiquimod is a TLR-7 agonist extensively used in the treatment of basal cell carcinoma (Urosevic et al, 2005).…”

Section: Tlrs and Anticancer Immunotherapymentioning

confidence: 99%

Exploitation of the Toll-like receptor system in cancer: a doubled-edged sword?

et al. 2006

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The toll-like receptor (TLR) system constitutes a pylogenetically ancient, evolutionary conserved, archetypal pattern recognition system, which underpins pathogen recognition by and activation of the immune system. Toll-like receptor agonists have long been used as immunoadjuvants in anti cancer immunotherapy. However, TLRs are increasingly implicated in human disease pathogenesis and an expanding body of both clinical and experimental evidence suggests that the neoplastic process may subvert TLR signalling pathways to advance cancer progression. Recent discoveries in the TLR system open a multitude of potential therapeutic avenues. Extrapolation of such TLR system manipulations to a clinical oncological setting demands care to prevent potentially deleterious activation of TLR-mediated survival pathways. Thus, the TLR system is a double-edge sword, which needs to be carefully wielded in the setting of neoplastic disease. METHODSReferenced papers were identified using multiple electronic searches of the Medline database with the keywords (alone or in combination): toll-like receptors (TLRs), cancer, TLR ligands, NFkB, innate immunity, acquired immunity and immunotherapy. The search strategy incorporated MESH terms, and results were evaluated for sensitivity and specificity. Additional articles were identified from the references of retrieved papers. Papers were included on the basis of evidence supporting individual points.

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Disease-Independent Skin Recruitment and Activation of Plasmacytoid Predendritic Cells Following Imiquimod Treatment

Abstract: Imiquimod induces immune activation patterns that relate to the number of the PDCs recruited to the treatment site, thus supporting the role of PDC in responsiveness to imiquimod in humans.

Cited by 171 publications

References 53 publications

Aldara activates TLR7-independent immune defence

Aldara activates TLR7-independent immune defence

TLR7 and TLR8 as targets in cancer therapy

Exploitation of the Toll-like receptor system in cancer: a doubled-edged sword?

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