Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells

Drobits, Barbara; Holcmann, Martin; Amberg, Nicole; Swiecki, Melissa; Grundtner, Roland; Hammer, Martina; Colonna, Marco; Sibilia, Maria

doi:10.1172/jci61034

Cited by 260 publications

(284 citation statements)

References 50 publications

Supporting

Mentioning

255

Contrasting

Unclassified

Order By: Relevance

“…Keratinocyte cell death was reduced in the presence of pan-caspase or caspase-1 inhibitors (Fig. 4c), which provides an explanation for the recently reported TLR7-independent death of keratinocytes 7 . Caspase-1-dependent lysis of keratinocytes is called 'pyroptosis', a mechanism that is distinct from apoptosis and independent of apoptosis-related caspases 41 .…”

Section: Article Nature Communications | Doi: 101038/ncomms2566supporting

confidence: 70%

“…4d), suggesting that Aldara activates the NLRP1 inflammasome. It was recently shown that IMQ itself induces apoptosis in a TLR7-independent fashion 7,19 , but there is no evidence that the Aldara vehicle can act on keratinocytes directly. We thus investigated whether IMQ or another component in the Aldara vehicle cream mediates inflammasome activation.…”

Section: Article Nature Communications | Doi: 101038/ncomms2566mentioning

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 . We and others previously showed that treatment with IMQ and Aldara resulted in upregulation of MHC class I on tumour cells, recruitment of T cells into the tumour, enhancement of their effector function and mobilization of Langerhans cells and inflammatory DCs, as well as in interleukin (IL)-17 production by dermal gd-T cells 8,[9][10][11][12] .…”

mentioning

confidence: 99%

“…Because keratinocytes do not express TLR7 7,16,17 , they presumably cannot respond directly to IMQ. Nevertheless, effects on keratinocytes have been described, such as induction of the secretion of IL-6, IL-8, TNFa and IL-1b by human primary keratinocytes in vitro, most likely via signalling through adenosine receptors 15,18,19 .…”

mentioning

confidence: 99%

See 4 more Smart Citations

Aldara activates TLR7-independent immune defence

et al. 2013

View full text Add to dashboard Cite

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.

show abstract

Section: Article Nature Communications | Doi: 101038/ncomms2566supporting

confidence: 70%

Section: Article Nature Communications | Doi: 101038/ncomms2566mentioning

confidence: 99%

Section: Aldara Induces Keratinocyte Proliferation In Human Nmscmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Aldara activates TLR7-independent immune defence

et al. 2013

View full text Add to dashboard Cite

show abstract

Toll‐like Receptors in Liver Disease

Kim

Seki

2020

The Liver

View full text Add to dashboard Cite

An Intelligent Nanovehicle Armed with Multifunctional Navigation for Precise Delivery of Toll‐Like Receptor 7/8 Agonist and Immunogenic Cell Death Amplifiers to Eliminate Solid Tumors and Trigger Durable Antitumor Immunity

Hao

Zhao

et al. 2022

Adv Healthcare Materials

View full text Add to dashboard Cite

Cancer immunotherapy is revolutionary in oncology and hematology. However, a low response rate restricts the clinical benefits of this therapy owing to inadequate T lymphocyte infiltration and low delivery efficiency of immunotherapeutic drugs. Herein, an intelligent nanovehicle (folic acid (FA)/1-(4-(aminomethyl) benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (IMDQ)-oxaliplatin (F/IMO)@CuS) armed with multifunctional navigation is designed for the accurate delivery of cargoes to tumor cells and dendritic cells (DCs), respectively. The nanovehicle is based on a near infrared-responsive inorganic CuS nanoparticles, acting as a photosensitizer and carrier of the chemotherapeutic agent oxaliplatin, and enters tumor cells owing to the presence of folic acid on the surface of CuS upon intratumoral injection. Furthermore, a toll-like receptor (TLR) 7/8 agonist-conjugated polymer, anchored on the surface of CuS, is modified with mannose to bind with DCs in the tumor microenvironment. Upon exposure to laser irradiation, nanovehicles disassemble, releasing oxaliplatin, to ablate tumor cells and amplify immunogenic cell death in combination with photothermal therapy. Mannose-modified polymer-TLR7/8 agonist conjugates are subsequently exposed, leading to the activation of DCs and proliferation of T cells. Collectively, these intelligent nanovehicles reduce tumor burden, exert a robust antitumor immune response, and generate long-term immune protection to prevent tumor recurrence.

show abstract

Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells

Abstract: Imiquimod is a synthetic compound with antitumor properties; a 5% cream formulation is successfully used to treat skin tumors. The antitumor effect of imiquimod is multifactorial, although its ability to modulate immune responses by triggering TLR7/8 is thought to be key.

Cited by 260 publications

References 50 publications

Aldara activates TLR7-independent immune defence

Aldara activates TLR7-independent immune defence

Toll‐like Receptors in Liver Disease

An Intelligent Nanovehicle Armed with Multifunctional Navigation for Precise Delivery of Toll‐Like Receptor 7/8 Agonist and Immunogenic Cell Death Amplifiers to Eliminate Solid Tumors and Trigger Durable Antitumor Immunity

Contact Info

Product

Resources

About