Ultraviolet light B (UVB; 290-320 nm) is a major environmental carcinogen that has been implicated in the development of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), collectively known as nonmelanoma skin cancers (NMSC). As highlighted by the recent Surgeon General's Call to Action, these skin tumors are the most common form of cancer in humans, with over 3.5 million new cases identified in the United States each year. It was recently estimated that between 3932 and 8791 individuals died from cutaneous SCC in the United States in 2012, just slightly fewer than deaths from melanoma. The mortality rate greatly increases in the immunosuppressed population such as solid organ transplant recipients (OTR). In these patients SCC is vastly over-represented compared with its frequency in non-immunosuppressed patients. Organ transplantation increases the risk of development of SCC by 65-200 fold. In fact the term catastrophic cutaneous carcinomatosis has been coined to describe the development of SCCs in these patients. Cases of catastrophic cutaneous carcinomatosis may require decreasing immunosuppressive therapy risking the loss of the transplanted organ. As seen in the immunocompetent population, sex plays a strong role, with immunosuppressed men having greater risk of developing SCC than women. Clearly more effective preventive and/or treatment strategies are needed to prevent the morbidity and mortality resulting from SCC development in these patients. Macrophage migration inhibitory factor (MIF) is an immunoregulatory cytokine that is overexpressed in several cancers including melanoma and head/neck SCC in humans. We have demonstrated in immune competent MIF KO and wild type mice treated with a pharmacological MIF inhibitor (MIFi) following chronic UVB exposure that this cytokine likewise contributes to the development of UVB- induced SCC of the skin. To date we are not aware of any studies examining the effects of immunosuppressive therapies on cutaneous levels of MIF. The studies in the current application will use this pre-clinical model to test the hypothesis that increases in UVB-induced SCC observed in OTR are mediated at least in part by elevated cutaneous MIF levels. Studies in Aim 1 will use the preclinical Skh-1 murine model to determine the efficacy of therapeutic intervention with a MIFi prior to the initiation of immunosuppressive therapy on UVB induced tumor development in the sexes. Studies in Aim 2 will determine the efficacy of MIFi treatment in inducing regression of established tumors in the sexes under an immunosuppressive environment. Completion of these studies will provide important information about a novel intervention/treatment strategy for catastrophic cutaneous carcinomatosis in OTR.
Non-melanoma skin cancers are the most common form of cancer in humans, with over 3.5 million new cases in the United States each year. Immunosuppressed patients, such as solid organ transplant patients develop these tumors in large numbers on sun-exposed sites significantly increasing morbidity and mortality for these patients. The studies in the current application will test a novel inhibitor of macrophage migration inhibitory factor in both preventio and regression of skin tumors in conjunction with immunosuppressive therapy.
