Imiquimod attenuates the growth of UVB‐Induced SCC in mice through Th1/Th17 cells

Abstract

Imiquimod (IMQ), a Toll-like receptor (TLR) 7/8 agonist, has been used to treat various skin neoplasms, including genital warts, actinic keratoses and superficial basal cell carcinomas. Although IMQ has been recognized to activate both innate and adaptive immunity, the underlying mechanism(s) by which IMQ exerts its anti-tumor activity in vivo remains largely unknown. In this study, we took advantage of skin cancer-prone mice to characterize the effects of IMQ on ultraviolet irradiation (UV)-induced de novo carcinogenesis. Transgenic mice with keratinocytes expressing constitutively activated Stat3 (K5.Stat3C mice) developed squamous cell carcinomas (SCC in situ) as early as after 14 weeks of UVB irradiation, while wild-type mice required much higher doses of UVB with more than 25 weeks of UVB irradiation to produce SCC. Topical treatment of K5.Stat3C mice with IMQ attenuated UVB-induced epidermal dysplasia (SCC in situ). In addition, SCC growth due to increased total irradiation doses was significantly attenuated by IMQ treatment. Topical IMQ treatment induced T cell and plasmacytoid dendritic cell infiltrates at the tumor sites, where levels of IL-12/23p40, IL-12p35, IL-23p19, IL-17A and IFN-γ mRNAs were up-regulated. Immunohistochemistry revealed T cell infiltrates consisting of T1, Th17 and CD8+ T cells. We speculate that topical IMQ treatment attenuates the de novo growth of UVB-induced SCC through activation of Th17/Th1 cells and cytotoxic T lymphocytes.

Ag-Presenting CpG-Activated pDCs Prime Th17 Cells That Induce Tumor Regression

“…Altogether, our data demonstrate that loss of MHCII expression by pDCs leads to impaired Th17 responses without affecting pDC innate functions and that CpG-activated pDCs function as efficient pro-Th17 bona fide APCs. Tissue infiltrating pDC numbers were correlated with the presence of Th17 cells in mucosa and skin of GvHD patients (41,42) and in mouse tumors (43,44). pDC depletion during EAE leads to impaired encephalitogenic Th17 responses and decreased clinical scores (3).…”

Therapeutic and immune effects of 5‐aminolevulinic acid photodynamic therapy on UVB‐induced squamous cell carcinomas in hairless mice

“…PDT generated inflammatory mediators together with components released from tumor cells can also activate antigen presenting cells capable of stimulating effector T-cell proliferation and cytokine secretion (11). Recently, Yokogawa et al (12) demonstrated that topical Imiquimod, a Toll-like receptor 7/8 agonist, could trigger T-cell infiltrates in SCCs. Because PDT and Imiquimod share similar pathways in modulating immune responses (13), it is important to explore the potential of PDT in inducing specific immunity against SCCs to shed light on the true value of PDT in SCC treatment.…”

Targeting Toll-like Receptors in Cancer Prevention

“…For example, imiquimod (Aldara), a TLR7 agonist, is effectively used to treat genital warts as well as superficial basal cell carcinoma (BCC). The mechanism by which imiquimod acts to eradicate these lesions is proposed to involve heightened immune response that includes activation of antitumor Th1/Th17 cells as well as induced apoptosis of tumor cells (6). The synthetic CpG oligodeoxynucleotide PF-3512676, a TLR9 agonist, has also been shown to demonstrate clinical activity in BCC (7).…”