UV Photodamage to the Skin: Prevention by Mutant p53 Immunization

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ABSTRACT Sunlight is the major environmental agent to which humans are exposed. Although it has beneficial effects (e.g. metabolism of vitamin D, energy necessary for life), chronic overexposure to the ultraviolet portion causes DNA damage, premature aging of the skin, immunosuppression and non-melanoma skin cancers (NMSCs) (i.e. cutaneous squamous cell and basal cell carcinomas). In the U.S. alone >5 million new NMSCs are treated each year. Though mortality from these malignancies is low, the overall socioeconomic burden exceeds $8 billion annually. Because of the clinical significance of the problem, there has been intense interest in identifying mechanisms by which UV radiation exerts its biologic effects and methods to prevent its adverse health effects. UV-induced skin cancers are highly immunogenic. In addition, approximately 90% of human SCCs and 50% of BCCs have mutations in the p53 tumor suppressor gene. The relationship between the immunogenicity of UV- induced skin cancers and mutations in p53 is an unexplored area of investigation. This provides the rationale for vaccinating against p53 mutations to evaluate its capacity to prevent the adverse effects of UV radiation. We hypothesize that immunization against mutant p53 will result in the generation of CD8+ T-cells that preferentially produce IFN-γ, which greatly reduce the mutations to which the immune response was generated, and, in turn, reduce the carcinogenic effects of this form of radiant energy. We will examine this issue by first identifying immunogenic mutant epitopes of p53 by assessing their ability in vitro and in vivo to stimulate T-cell-derived cytokines and a cell-mediated immune response in mice. The immunization procedure will be evaluated in vaccination mice for its efficacy in preventing UV-induced p53 mutations to which the immune response is directed and in reducing the incidence of UV-induced tumors caused by those mutations. The ultimate goal of these studies will be to assess whether UV-induced tumors can be prevented by mutant p53 vaccination.