Imiquimod Enhances IFN-γ Production and Effector Function of T Cells Infiltrating Human Squamous Cell Carcinomas of the Skin

Abstract

Squamous cell carcinomas (SCC) are sun-induced skin cancers that are particularly numerous and aggressive in patients taking T cell immunosuppressant medications. Imiquimod is a topical immune response modifier and TLR7 agonist that induces the immunologic destruction of SCC and other skin cancers. TLR7 activation by imiquimod has pleiotropic effects on innate immune cells but its effects on T cells remain largely uncharacterized. Because tumor destruction and formation of immunologic memory are ultimately T cell mediated effects, we studied the effects of imiquimod therapy on effector T cells infiltrating human SCC. SCC treated with imiquimod prior to excision contained dense T cell infiltrates associated with tumor cell apoptosis and histologic evidence of tumor regression. Effector T cells from treated SCC produced more IFN-γ, granzyme and perforin and less IL-10 and TGF-β than T cells from untreated tumors. Treatment of normal human skin with imiquimod induced activation of resident T cells and reduced IL-10 production but had no effect on IFN-γ, perforin or granzyme, suggesting that these latter effects arise from recruitment of distinct populations of T cells into tumors. Thus, imiquimod stimulates tumor destruction by recruiting cutaneous effector T cells from blood and by inhibiting tonic anti-inflammatory signals within the tumor.

Cancer-Testis Antigens and Immunosurveillance in Human Cutaneous Squamous Cell and Basal Cell Carcinomas

“…In contrast, treatment with IFN-γ (100 units/mL) induced increased surface expression of β 2 -microglobulin as well as HLA-A,B,C molecules at least by 2-fold (assessed by measuring mean fluorescence intensity by flow cytometry; data not shown). Alternatively, treatment with imiquimod may induce changes in the microenvironment other than upregulation of MHC-I molecules that support local tumor-specific CD8 + T cells, as has been reported for SCC (5,34). Because the CD8 + T cells of imiquimod-treated BCC patients remain in the peritumoral region and do not seem to penetrate the BCC nests (Fig.…”

Aldara activates TLR7-independent immune defence

“…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] .…”

TLR receptors in laryngeal carcinoma - immunophenotypic, molecular and functional studies.

“…For example imiquimod, man-made ligand for TLR7, was shown to inhibit growth of skin carcinoma when applied as an ointment [12,13]. The positive effect of imiquimod was found to be immunologically mediated, because it was due up-regulation of effector function of T cells [14].…”