Non-melanoma (basal cell and cutaneous squamous cell carcinomas) skin cancer and melanoma are common human malignancies whose growth is controlled at least in part by T-lymphocyte mediate immune responses. There is great interest in developing new modalities which will enhance and exploit this host defense mechanism for therapeutic benefit. We have observed that cutaneous squamous cell carcinomas and melanomas exhibit a profound reduction in tumor growth when treated with the bacterial super- antigen Staphylococcal enterotoxin B (SEB). The response is immunologic in nature and is highly specific for malignant tissue, both in vivo and in vitro. SEB may thus have great potential as a immunodermatologic therapy for skin cancer. In this proposal, we plan to investigate the hypothesis that the bacterial super-antigen SEB causes selective destruction of non- melanoma and melanoma skin cancers by serving as a ligand between the tumor cell and cytotoxic T-lymphocytes. We will more fully assess the immunodermatologic potential of SEB as a therapy for skin cancer by studying the range of cutaneous tumors responsive to SEB immunodermatologic therapy. We will also assess the efficacy of mutants SEB as therapeutic agents in skin cancer in order to identify those regions of the molecule most important at causing regression of skin cancers. Studies will be performed to evaluate whether inhibition of tumor cell growth by SEB and T-cells is cytotoxic in nature. Experiments will be conducted to identify the molecule on cutaneous squamous cell carcinomas to which SEB binds that allows it to inhibit the growth of cutaneous tumors. We will be particularly interested in determining whether SEB binding to major histocompatibility complex class I and class II molecules plays a role in the response. Because SEB limits the growth of malignant cells, but has little effect on keratinocytes from which these tumors are derived, we will investigate whether this is due to differential binding on SEB to tumor cells versus normal keratinocytes, differences in the expression of the adhesion molecule ICAM-1 on these two cell types, or to differences in the Fas pathway in normal versus malignant keratinocytes. Finally, experiments will be performed to precisely define the characteristics of the T-cell most effective at causing SEB-induced regression of cutaneous tumors. The ultimate goal of this proposal is to generate new knowledge that can be used to develop new and better strategies for the control of non-melanoma and melanoma skin cancer.
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