UV Photodamage to the Skin: Prevention by Mutant p53 Immunization

摘要 阳光是人类暴露在环境中的主要因素。虽然它有有益的影响(例如 维生素D的新陈代谢，生命所必需的能量)，长期过度暴露在紫外线部分会导致DNA 损伤、皮肤过早老化、免疫抑制和非黑色素瘤皮肤癌(NMSCs)(即 皮肤鳞状细胞癌和基底细胞癌)。仅在美国，就有500万个新的NMSCs接受治疗 年。尽管这些恶性肿瘤的死亡率很低，但总的社会经济负担超过80亿美元。 每年一次。由于这一问题的临床意义，人们一直对确定 紫外线辐射发挥其生物效应的机制和预防其不良健康影响的方法。 紫外线诱发的皮肤癌具有很强的免疫原性。此外，大约90%的人类干细胞和50%的 膀胱移行细胞癌存在p53肿瘤抑制基因突变。紫外线免疫原性与免疫原性的关系 诱发皮肤癌和P53突变是一个未被探索的研究领域。这就提供了理论基础 用于接种针对p53突变的疫苗，以评估其预防紫外线辐射不良影响的能力。我们 假设针对突变型p53的免疫将导致CD8+T细胞的产生，而CD8+T细胞优先 产生干扰素-γ，大大减少产生免疫反应的突变，反过来， 减少这种形式的辐射能量的致癌作用。我们将首先确定以下内容来研究此问题 免疫原性突变型P53表位体内外刺激T细胞分化能力的研究 细胞因子与小鼠的细胞免疫反应。免疫接种程序将于#年进行评估。 给小鼠接种疫苗，以防止紫外线诱导的免疫应答所致的p53突变 目的是为了减少由这些突变引起的紫外线诱导肿瘤的发生率。的最终目标是 这些研究将评估紫外线诱导的肿瘤是否可以通过突变的p53疫苗预防。

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.