Our findings confirmed the association of ultraviolet radiation exposure with development of CSCC in OTR. The increased depth of the primary CSCC in OTR is surprising because these patients are followed closely for skin cancer compared with immunocompetent patients. The other morphologic features that were significantly more common in OTR may theoretically reflect not only the type of iatrogenic immunosuppression in these patients, but also other procarcinogenic effects of their medications.
Development of cutaneous SCCs appears to be a side effect limited to sorafenib, a multikinase inhibitor that inhibits not only multiple tyrosine kinases (TKs), but also the serine-threonine kinase Raf. The incidence of cutaneous SCCs does not appear greater with multikinase inhibitors that inhibit only TKs.
The imidazoquinolines arose from efforts to develop a nucleoside analogue. Although molecularly similar to nucleosides, the imidazoquinolines did not have nucleoside-like activity. However, the imidazoquinolines induced immune modulatory cytokines, in part, because of their ability to activate toll receptors (TLR)s. Imiquimod, the first FDA-approved imidazoquinoline, has been marketed as a 5% cream, which is approved for the therapy of genital warts. The advantage of imiquimod therapy over other therapies for genital warts is the decrease in recurrence rate with the establishment of an adaptive immunological response or immunological memory/surveillance response. As tumours and viral infections are handled similarly by the immune system, there has been great interest in the use of topical imiquimod for the treatment of cutaneous neoplasms, particularly non-melanoma skin cancers. Future efforts in imidazoquinoline research is focused around the development of analogues with modifications in the immunological profiles, potency and penetration parameters that better focus these new analogues for the therapy of specific intracellular infections and neoplasms, as well as the development of imidazoquinolines for conditions related either directly or indirectly to patterns of immune dysregulation.
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.
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