Mechanisms Underlying Imiquimod-Induced Regression of Basal Cell Carcinoma In Vivo

Urosevic, Mirjana; Maier, Tanja; Benninghoff, Bernd; Slade, Herbert B.; Burg, G.; Dummer, Reinhard

doi:10.1001/archderm.139.10.1325

Cited by 131 publications

(133 citation statements)

References 42 publications

(65 reference statements)

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“…Overall, although some aspects of the TLR-dependent activity of imiquimod and related compounds are not entirely clear yet, there is compelling evidence for the notion that imiquimod-through stimulation of antitumoral T cells following activation of antigen presenting cells as well as through direct antitumoral activation of dendritic cell subsets-exerts its activity primarily at the interface between innate and acquired immunity (Hurwitz et al, 2003;Urosevic et al, 2003).…”

Section: Cellular Immune Reactions Induced By Imidazoquinolinesmentioning

confidence: 99%

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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Section: Cellular Immune Reactions Induced By Imidazoquinolinesmentioning

confidence: 99%

TLR7 and TLR8 as targets in cancer therapy

2008

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“…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 .…”

mentioning

confidence: 99%

“…In addition to effects on immune cells, direct pro-apoptotic effects of Aldara/IMQ on tumour cells have been described 5,[13][14][15] . Because keratinocytes do not express TLR7 7,16,17 , they presumably cannot respond directly to IMQ.…”

mentioning

confidence: 99%

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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“…However, there are discrepant results regarding IL-10 expression in superficial BCC. Urosevic et al found that superficial BCC cells were uniformly negative for IL-10 expression at baseline and showed little change after imiquimod treatment (19). www.intechopen.com SNP in the promoter regions of IL-10 gene (IL10) is associated with the risk of BCC.…”

Section: Il-10mentioning

confidence: 99%

“…IFN-γ is associated with the enhanced expression of ICAM-1, promoting the influx of immune cells. Imiquimod treatment also induces a massive increase in macrophage peritumoral and intratumoral infiltration (19). Thus, the TLR7-agonist plays an important role in inducing a lymphocytic infiltrate by promoting specific Th1 cellular immune response capable of eliminating cancer cells (34).…”

Section: Ifn-γmentioning

confidence: 99%

The Role of Cytokines and Chemokines in the Development of Basal Cell Carcinoma

Itakura¹

2012

Basal Cell Carcinoma

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Mechanisms Underlying Imiquimod-Induced Regression of Basal Cell Carcinoma In Vivo

Cited by 131 publications

References 42 publications

TLR7 and TLR8 as targets in cancer therapy

TLR7 and TLR8 as targets in cancer therapy

Aldara activates TLR7-independent immune defence

The Role of Cytokines and Chemokines in the Development of Basal Cell Carcinoma

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