Therapeutic immunosuppression, inflammation & skin cancer

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DESCRIPTION (provided by applicant): The past 30 years have seen unprecedented growth in the numbers of immunosuppressed patients. These include patients with disease-related immunosuppression, such as those infected with HIV, as well as those receiving long-term therapeutic immunosuppression including transplant patients and patients with inflammatory and autoimmune disorders. While the degree of immunosuppression varies considerably among these patients, common findings are a dampening of T-cell function and a dramatic increase in the development of ultraviolet light (UV)-induced cutaneous squamous cell carcinoma (SCC). Not only is the incidence of SCC higher in these patients than in the general population but the number of SCC that develop in each patient is increased. The SCC arising in immunosuppressed 90 patients are often very aggressive and are associated with substantial mortality. While it is clear that UV exposure and immunosuppression are major factors in the development of cutaneous malignancies, it is not clear how diminished T cell responses, either as a byproduct of disease or as a result of therapy, contributes to the generation of SCC. The following specific aims are designed to test the hypothesis that selective depletion of CD4 T-cells increases the UVB-induced inflammatory response in the skin and that this, in turn, results in an earlier onset of SCC, increased numbers of SCC, and increased aggressiveness of the tumors. These studies will also examine the importance of timing of immunosuppression relative to UV exposure on SCC development. Studies in specific Aim 1 will examine the effects of depleting CD4+ T-cells or decreasing function of these cells by treating with the therapeutically relevant immunosuppressive agent cyclosporine concurrently with DVB exposure on UVB-induced inflammation and tumor formation, in an SKH-1 hairless mouse model of UVB-induced SCC development. This aim examines the effects of T-cell dysregulation concurrently with UV exposure, as would be seen in children who are immunosuppressed early life, before they have accumulated substantial UVB exposure. Studies in specific Aim 2 will examine the effects of CD4* T-cell depletion or cyclosporine treatment begun after 10 weeks of UVB exposure on inflammation and tumor formation in SKH-1 hairless mice. This aim examines the effects of T-cell dysregulation following prior UVB exposure, as would be seen in adults who have had significant UVB exposure prior to immunosuppression. Studies in specific Aim 3 will determine the effects of CD4 T-cell depletion or cyclosporine treatment begun after 20 weeks of UVB exposure on the progression of papillomas to SCC in SKH-1 hairless mice. This aim examines the effects of T-cell dysregulation on the progression and aggressiveness of established UVB induced tumors. The studies in the present proposal will help to clarify the role of CD4* T cells in UVB induced inflammation as well as in the cutaneous carcinogenesis process.