Topical imidazoquinoline therapy of cutaneous squamous cell carcinoma polarizes lymphoid and monocyte/macrophage populations to a Th1 and M1 cytokine pattern

Abstract

Imidazoquinolines are topical immune response modifiers. Imiquimod (IMI), the first imidazoquinoline, is approved for the treatment of genital human papillomavirus disease and has shown success as a therapeutic agent for cutaneous premalignant and malignant tumours. To define the pattern of polarization of the local immune response to invasive cutaneous squamous cell carcinoma (SCC) we pretreated 10 SCCs that were > 3 cm in diameter for 2 weeks with IMI. The tumours were treated on Monday, Wednesday and Friday and excised the next Monday. A battery of immunohistochemical markers was used to define the mononuclear cell populations in the diagnostic, and the excisional biopsy specimens. The total inflammatory infiltrate was increased after IMI therapy: the greatest increase was in the CD8 T cells with a marked relative decrease in the CD68 monocytic/macrophages; the majority of the CD8 T cells showed expression of cytotoxic granules, T cell-restricted intracellular antigen (TIA) and granzyme B. The relative numbers of monocytes/macrophages were decreased after therapy with IMI with a decrease in CD68+, CD23+, and CD14+ cells and an increase in MAC-397+, and factor XIIIa+ cells. The epidermal dendritic cells showed a > 75% decrease in CD1a+ cells. The immunohistochemical marker profile after IMI therapy is consistent with that induced by a Th1 and M1 cytokine polarization pattern. This cytokine pattern is known to be more effective in defence against tumours as well as viral infections.

Platelet-derived Growth Factor-C (PDGF-C) Induces Anti-apoptotic Effects on Macrophages through Akt and Bad Phosphorylation

“…These findings have led to an evaluation of macrophage targeting in a tumor setting (46 -48). The fundamental principles of TAM-targeted anti-tumor approaches are based on inhibiting macrophage recruitment (49 -51), suppressing TAM survival (52)(53)(54), enhancing the anti-tumor activity of TAMs (55)(56)(57), and blocking their protumor activity (58 -60). Targeting TAMs is thus an important and efficient strategy for cancer therapy.…”

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

“…TLR7/8 agonists lead to better priming of CTLs by efficient maturation and activation of APCs [62,65], and CD8 ϩ T cells showed a higher expression level of perforin and cytotoxic granule markers [64,66]. Imiquimod not only enhanced DC migration but also induced migration of human CD4 ϩ and CD8 ϩ T cells toward the place of topical treatment [54,67,68].…”

“…ϩ T-cell responses [60 -62], at least partially mediated by the induced Th1-polarizing cytokine pattern [63,64]. TLR7/8 agonists lead to better priming of CTLs by efficient maturation and activation of APCs [62,65], and CD8 ϩ T cells showed a higher expression level of perforin and cytotoxic granule markers [64,66].…”

Imidazoquinoline Acts as Immune Adjuvant for Functional Alteration of Thymic Stromal Lymphopoietin-Mediated Allergic T Cell Response

“…Notably, on the basis of our results, R848 appears to exhibit its function not only in the priming phase of DCs by TSLP but also in the later phase of priming T cells by TSLP-DCs. In addition to these specialized roles of R848 for DCs in allergic responses, there may be a great advantage; that is, because imidazoquinoline has already been used to topically treat viral-mediated skin diseases by cream formulation (62)(63)(64)(65), this imidazoquinoline drug could be used without systemic side effects when R848 is clinically applied for the treatment of atopic dermatitis.…”