Primary melanoma of the skin occurs in a variety of phenotypes. It may present as a slowly enlarging, heterogeneously pigmented macule where transformed melanocytes spread horizontally in the epidermis and upper dermis associated with lymphocytic infiltrates and tumor regression. It may also appear as a progressively growing, darkly pigmented nodule where melanoma cells invade vertically into the dermis in the absence of immune cell infiltration and rapidly spread to regional lymph nodes and visceral organs (Tsao et al., 2004). Tumor biologists have uncovered differences in the molecular pathogenesis of melanoma that correlate with the variations in biological behavior. Tumor immunologists have gained insights how lymphocytes recognize and destroy melanoma cells. However, the relationship between tumor biology and tumor immune defense and the mechanisms determining the balance between tumor regression and tumor progression in the microenvironment of primary and metastatic melanomas are poorly understood (Prendergast and Jaffee, 2007).
The development of genetically engineered mouse tumor models based on insights in the molecular pathogenesis of human melanoma provides novel opportunities to investigate the interaction between tumor and immune cells in the microenvironment of primary melanomas. Our group has established such a model, the Hgf-Cdk4R24C mouse, which imitates not only the molecular pathogenesis but also the histomorphology of darkly pigmented nodular melanoma in man. The aims of this project are to characterize the regulation of cytotoxic T cell functions and the role of type I interferons in the tumor microenvironment of primary and metastatic Hgf-Cdk4R24C melanoma and to utilize this information for the improvement of chemo-immunotherapies targeting innate and adaptive cytotoxic tumor immune defense.