UV Photodamage to the Skin: Prevention by Mutant p53 Immunization

摘要 阳光是人类接触的主要环境因素。虽然它具有良好的效果（例如， 维生素D的代谢，生命所需的能量），长期过度暴露于紫外线部分会导致DNA 损伤、皮肤过早老化、免疫抑制和非黑色素瘤皮肤癌（NMSC）（即， 皮肤鳞状细胞癌和基底细胞癌）。仅在美国，就有超过500万新的NMSC接受治疗， 年虽然这些恶性肿瘤的死亡率很低，但总体社会经济负担超过80亿美元 每年。由于这个问题的临床意义，人们对识别 紫外线辐射发挥其生物效应的机制和防止其对健康不利影响的方法。 紫外线诱发的皮肤癌具有高度免疫原性。此外，大约90%的人类SCC和50%的 BCC在p53肿瘤抑制基因中具有突变。紫外线照射与免疫原性的关系 诱导的皮肤癌和p53突变是一个未探索的研究领域。这提供了理由 用于针对p53突变的疫苗接种，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免疫将导致产生CD 8 + T细胞， 产生IFN-γ，这大大减少了产生免疫应答的突变，反过来， 减少这种形式的辐射能的致癌作用。我们将通过首先确定 通过评估p53的免疫原性突变表位在体外和体内刺激T细胞来源的免疫原性表位的能力， 细胞因子和细胞介导的免疫应答。免疫程序将在 疫苗接种小鼠，以观察其在预防UV诱导的p53突变中的功效， 指导和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 这些研究将评估突变型p53疫苗接种是否可以预防UV诱导的肿瘤。

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.