Host Defense Mechanisms in Polyaromatic Hydrogen Carcinogenesis

多环芳烃致癌过程中的宿主防御机制

• 批准号: 8242611
• 负责人: Craig A Elmets
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242611
• 关键词: 3-Methylcholanthrene; Animals; Anthracenes; Antibodies; Antigens; Automobiles; Award; Benzo(a)pyrene; Biological Models; Bladder; Breast; Burn injury; CD8B1 gene; Cancer Etiology; Carcinogens; Carcinoma; Cell Line; Cellular Immunity; Charcoal; Chemicals; Clinical; Codon Nucleotides; Complex; Cutaneous; Dendritic Cells; Development; Effector Cell; Environmental Carcinogens; Evaluation; Event; Experimental Models; Exposure to; Food; Fossil Fuels; Funding; Generations; Goals; Gulf War; HRAS gene; Head and Neck Cancer; Health; Histocompatibility Antigens Class I; Host Defense Mechanism; Hydrocarbons; Hydrogen; Immune response; Immune system; Immunity; Individual; Interleukin-12; Kuwait; Malignant Neoplasms; Malignant neoplasm of lung; Methods; Modeling; Mus; Mutation; Occupational Malignant Neoplasm; Oncogenes; Papilloma; Pathway interactions; Persian Gulf; Play; Point Mutation; Population; Premalignant; Prevention; Procedures; Process; Proteins; Reagent; Research; Resistance; Role; Skin; Skin Cancer; Skin Carcinogenesis; Skin Neoplasms; Smoker; Staging; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tobacco smoke; Topical application; Ubiquitin; Vaccinated; Vaccination; Vaccines; Veterans; antigen processing; base; beneficiary; carcinogenesis; cell mediated immune response; chemical carcinogenesis; cigarette smoking; cytokine; design; dimethylbenzanthracene; environmental mutagens; genetic immunization strategies; interest; interleukin-23; multicatalytic endopeptidase complex; mutant; novel; prevent; prototype; response; tumor; tumor progression; tumorigenesis; vaccination strategy; vector

DESCRIPTION (provided by applicant): Polyaromatic hydrocarbons are ubiquitous environmental compounds that are the major carcinogenic moiety in cigarette smoke and were present in the burning oilfield emissions in the Persian Gulf War. There has been intense experimental interest in identifying the mechanisms by which they cause cancer. It is now known that the polyaromatic hydrocarbon 7,12- dimethylbenz(a)anthracene (DMBA) produces a specific point mutation in 61st codon of the H- ras oncogene and that this mutation is necessary for tumors to develop. While it is clear that the tumors caused by carcinogenic polyaromatic hydrocarbons elicit a partially protective immune response, the role that T-cell mediated immunity plays at earlier stages in the cutaneous carcinogenesis pathway is not well-understood. Our studies funded through a VA Merit Review Award have shown that administration of DMBA to the skin of mice results in an antigen specific T-cell mediated immune response that confers resistance to DMBA-induced tumor development. The T-cell response is directed, at least in part, at the H-ras mutation in the 61st codon and an immune response to the endogenous non-mutated ras does not occur. Based on these findings, we hypothesize that vaccination strategies resulting T-cell mediated immunity to oncogene mutations produced by polyaromatic hydrocarbons serves to protect individuals against the carcinogenic effects of these agents, and efforts to amplify that response will further reduce the formation of polyaromatic hydrocarbon-induced cancers. To test our hypothesis, we have prepared a genetic-immunization vector containing a ubiquitin-mutant ras fusion minigene sequence which provides superior proteosome targeting of the encoded protein. This promotes MHC class I antigen processing and thereby enhances the generation of CD8+ T-cells. We have developed stable dendritic cell lines transfected with our vector, and intend to us them to vaccinate animals to establish whether they will prevent the DMBA-induced skin tumors. We will also evaluate the effect of dendritic cell vaccination with our vector on activation of T-cell subsets and on their cytokine profiles. Studies are planned to assess the effect of dendritic cell vaccination with mutant H-ras on the presence of H-ras mutations in tumors and in non-tumor-bearing DMBA treated skin. Finally, we will determine the role of IL-12 and IL-23 in the T-cell response to mutant H-ras and whether administration of these cytokines or their neutralization through antibody treatment will alter the efficacy of the vaccination procedure. The long-term goal of these studies is to identify methods for the immunoprevention of tumors caused by carcinogenic polyaromatic hydrocarbons. Veterans are likely to be among the major beneficiaries of such methods because of the high proportion of smokers in this population and because of their exposure to these agents during the Persian Gulf War. PUBLIC HEALTH RELEVANCE: There is great interest in identifying the mechanisms by which chemicals cause cancer. This is especially true for polyaromatic hydrocarbons (PAHs), carcinogens that are present in cigarette smoke, charcoal broiled food, and were found in burning oilfields during the Persian Gulf War. PAHs are a major, if not the major, cancer producing agents among veterans. They cause lung cancer and have been implicated in cancers of the head and neck, bladder and breast. The skin is an important experimental model to define processes by which PAHs cause cancer, since it is easily accessible and tumors can be readily identified. Our studies suggest that there are important interactions between the immune system, PAHs and the mutations that PAHs produce. We have developed novel reagents and we utilize them as a vaccine to determine if they augment immunity to PAHs and can be used to prevent tumors from developing in the first place.

描述（由申请人提供）： 多环芳烃是普遍存在的环境化合物，是香烟烟雾中的主要致癌成分，并且存在于波斯湾战争中燃烧的油田排放物中。人们对确定它们导致癌症的机制产生了浓厚的实验兴趣。现在已知多环芳烃7,12-二甲基苯并(a)蒽(DMBA)在H-ras癌基因的第61个密码子中产生特定的点突变，并且该突变是肿瘤发生所必需的。虽然很明显，由致癌多环芳烃引起的肿瘤会引起部分保护性免疫反应，但 T 细胞介导的免疫在皮肤癌发生途径的早期阶段所起的作用尚不清楚。我们通过 VA 优异评审奖资助的研究表明，向小鼠皮肤施用 DMBA 会产生抗原特异性 T 细胞介导的免疫反应，从而抵抗 DMBA 诱导的肿瘤发展。 T 细胞反应至少部分针对第 61 个密码子中的 H-ras 突变，并且不会发生针对内源性非突变 ras 的免疫反应。基于这些发现，我们假设疫苗接种策略导致 T 细胞介导对多环芳烃产生的癌基因突变的免疫，可以保护个体免受这些物质的致癌作用，而放大这种反应的努力将进一步减少多环芳烃诱发的癌症的形成。为了检验我们的假设，我们制备了包含泛素突变体 ras 融合小基因序列的基因免疫载体，该序列为编码的蛋白质提供了卓越的蛋白酶体靶向性。这促进 MHC I 类抗原加工，从而增强 CD8+ T 细胞的生成。我们已经开发出用我们的载体转染的稳定树突状细胞系，并打算用它们给动物接种疫苗，以确定它们是否能预防 DMBA 诱导的皮肤肿瘤。我们还将评估使用我们的载体进行树突状细胞疫苗接种对 T 细胞亚群激活及其细胞因子谱的影响。计划开展研究评估树突状细胞疫苗接种突变型 H-ras 对肿瘤和非肿瘤 DMBA 治疗皮肤中 H-ras 突变存在的影响。最后，我们将确定 IL-12 和 IL-23 在 T 细胞对突变型 H-ras 的反应中的作用，以及这些细胞因子的施用或通过抗体治疗中和它们是否会改变疫苗接种程序的功效。这些研究的长期目标是确定对致癌多环芳烃引起的肿瘤进行免疫预防的方法。退伍军人可能是此类方法的主要受益者之一，因为该人群中吸烟者的比例很高，而且他们在波斯湾战争期间接触过这些药物。 公共卫生相关性： 人们对确定化学物质导致癌症的机制非常感兴趣。对于多环芳烃 (PAH) 来说尤其如此，这种致癌物质存在于香烟烟雾、木炭烧烤食品中，并且在波斯湾战争期间在燃烧的油田中发现了这种物质。多环芳烃即使不是退伍军人中主要的致癌因素，也是主要的致癌因素。它们会导致肺癌，并与头颈癌、膀胱癌和乳腺癌有关。皮肤是定义多环芳烃导致癌症过程的重要实验模型，因为它很容易接近并且可以轻松识别肿瘤。我们的研究表明，免疫系统、多环芳烃和多环芳烃产生的突变之间存在重要的相互作用。我们开发了新型试剂，并将它们用作疫苗，以确定它们是否能增强对多环芳烃的免疫力，并可用于从一开始就预防肿瘤的发展。