Mast cells and immunosuppression in skin cancer

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DESCRIPTION (provided by applicant): Non-melanoma skin cancers (NMSCs), which include basal and squamous cell carcinomas, are the most commonly diagnosed cancers. The incidence of these cancers is increasing at an alarming rate in the general population and the risk is significantly higher in people that have received solid organ transplants. Transplant recipients have a 65-250 fold increased risk of developing NMSC compared to the rest of the population. Unfortunately, these patients develop a high number of NMSCs with a larger proportion of squamous cell carcinomas (SCCs), and the tumors that arise tend to be highly aggressive and metastasize more frequently. The reason for this abnormally high prevalence in SCC in transplant patients is not clear; however, suppression of the immune system, which can diminish the detection and destruction of tumor cells, is thought to be important. Transplant patients have reduced immune function due to the immunosuppressive drugs they must take to maintain tolerance and prevent rejection of the transplanted organ. In addition, exposure to ultraviolet light (UV) from the sun, regarded as the largest risk factor and etiologic agent of NMSC, also suppresses the immune system. The immunosuppressive drugs and the immunosuppressive effects of cumulative UV exposure likely work in concert to increase the NMSC risk in transplant recipients. Recent studies have demonstrated that cyclosporine A, an immunosuppressive drug commonly taken by transplant patients, alters skin carcinogenesis. In mouse models, exposure to UV followed by systemic treatment with cyclosporine results in larger tumors and a higher percentage of malignant SCCs than control mice. In addition to affecting characteristics of the tumors, our preliminary data indicate that the number of dermal mast cells increases significantly in cyclosporine-treated mice compared to vehicle controls after chronic UV irradiation. Mast cells have recently been shown to be critical regulators of the immunosuppressive effects of UV; however, the importance of the immunosuppressive effects of mast cells on skin carcinogenesis after chronic UV exposure is not known. The central hypothesis of the proposed studies is that CsA enhances skin carcinogenesis by stimulating immunosuppressive properties of dermal mast cells. To test this hypothesis, the following specific aims will be carried out: Aim 1 - Examine the importance of mast cells to CsA-mediated tumor progression; Aim 2 - Determine direct effects of CsA on dermal mast cells. The results of these experiments will generate new information about the contribution of mast cells to the development and growth of UV-induced skin tumors both in a normal setting and in the presence of immunosuppressive drugs.