Host Defense Mechanisms in Melanoma Pathogenesis

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 DESCRIPTION (provided by applicant): Melanomas are responsible for more deaths than any other cutaneous malignancy. They are a particular problem for Veterans who have extensive exposure to its two most common etiologic factors - ultraviolet radiation and carcinogenic polyaromatic hydrocarbons, and who have been shown to be at increased risk for this type of malignancy. There has been substantial progress in the treatment of advanced and metastatic melanomas. Many melanomas begin as premalignant dysplastic nevi, which after months to years, progress to become progress to become invasive neoplasms. Despite the fact that there is a long lag period before premalignant dysplastic nevi become invasive melanomas, there has been little headway in the development of methods for their prevention. This is due at least in part to the fact that there are few animal models that can evaluate preventive strategies. We have created a murine model of melanoma development in which pigmented lesions begin as preneoplastic dysplastic nevi and then evolve into invasive melanomas that metastasize to lymph nodes. RAS mutations and deletions in p16, both of which are common in human melanomas are present in the pigmented lesions. This contrasts with other murine models of melanoma, in which melanomas rapidly develop without the prior existence of dysplastic nevi. In addition, it is difficult to study host immune responsesin these other models, because mutant genes are present in all tissue specific cells as defined by the transgene promoter. We have observed that the cytokine IL-23 prevents the development of melanoma in this model. We have also found that immunization of mice against the mutant RAS protein will prevent non-melanoma skin cancers that express the mutation from developing. In this proposal, we will test the hypothesis that the cytokine IL-23 protects against melanomas and their metastases. We will first evaluate whether molecular alterations that participate in the pathogenesis of melanoma occur more frequently in IL-23KO mice and whether administration of IL-23 can be used as an immunopreventive agent. We will then characterize the role of IL-17 in the genesis of melanocytic tumors. Last, we will determine whether the immunization procedure we have successfully employed for prevention of non-melanoma skin cancers can be used to prevent tumor growth and the metastatic potential of melanomas. The findings of this application may form the foundation for new immunopreventive strategies for this malignancy that is occurring with increasing frequency in Veterans.