The research proposed here is an ongoing inquiry into the immunogenicity, cellular host response and related natural history of human cutaneous melanoma and its precursor lesions. Central to this effort are a large, well studies group of patients with melanoma and precursor pigmented lesions; patient-derived host immune cells and lesional cell lines and short-term cultures; and monoclonal antibodies directed to melanoma-associated antigens and HLA class II antigens. With these resources we have found a fundamental difference in the behavior of cell lines established from biologically early primary melanoma and advanced disease. Cells cultured from early primary melanomas activate and stimulate the proliferation of autologous T cells. These, in turn, are cytotoxic to autologous tumor and produce immunomodulatory cytokines. Expression of class II antigens is necessary but insufficient for melanoma cells to stimulate. Melanoma cells derived from advanced disease (late primary disease and metastases) are not stimulatory. Companion immunohistologic studies confirm in vivo parallels to these observations. Current and proposed studies are directed to three specific aims: 1) a functional, phenotypic and structural analysis of tumor-associated class II antigens from primary, stimulating melanoma lines and those of advanced, non-stimulating disease to delineate what is hypothesized to be a general structural and functional abnormality of such antigens in advancing tumor progression; 2) identification of melanoma-associated antigens which, in concert with class II antigens, are hypothesized to provoke lymphocyte stimulation; and, 3) a functional and biochemical analysis of cytokines produced by lesional melanocytic cells which potentially influence the cellular immune response to evolving melanoma and the tumor environment. These studies should contribute to an understanding of the role of host cellular immunity in the development biology of melanoma. Such studies are of general importance to tumor immunology as melanoma is uniquely succeptible, because of its easy detection and accessibility in the skin, to investigations while the early and, presumably most important, host-tumor interactions are taking place. An understanding of these interactions should lead to strategies both to reveal fundamental mechanisms underlying tumor progression and to suggest novel therapeutic approaches.
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