The Role of Allergic Contact Dermatitis in Skin Carcinogenesis

过敏性接触性皮炎在皮肤癌发生中的作用

• 批准号: 9326818
• 负责人: Shadmehr Demehri
• 金额: $ 17.85万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326818
• 关键词: Acute; Address; Adoptive Cell Transfers; Adverse event; Affect; Allergens; Allergic Contact Dermatitis; Animals; Antibodies; B-Lymphocytes; Cancer Biology; Carcinogens; Cardiac; Cells; Chronic; Chronic Phase; Clinical; Contact hypersensitivity; Cytotoxic T-Lymphocytes; Dental; Developed Countries; Development; Devices; Dinitrofluorobenzene; Environment; Equilibrium; Exanthema; Exposure to; General Population; Goals; Human; Hypersensitivity; IgE; Immune; Immune response; Immunity; Immunotherapeutic agent; Implant; Individual; Inflammation; Inflammatory; Interleukin-4; Interleukin-6; Malignant Neoplasms; Mediating; Medical; Medical Device; Metals; Methods; Molecular; Mus; Natural Killer Cells; Nickel; Organ; Orthopedics; Outcome Study; Outcomes Research; Patients; Prevalence; Property; Pruritus; Publications; Regulatory T-Lymphocyte; Reporting; Research; Role; Site; Skin; Skin Cancer; Skin Carcinogenesis; Skin Neoplasms; Source; Squamous cell carcinoma; TSLP gene; Testing; Th1 Cells; Therapeutic Uses; Time; Tumor Immunity; Tumor Promoters; Tumor Promotion; Tumor Suppression; Tumorigenicity; United States; base; cancer immunotherapy; carcinogenicity; cell type; clinically relevant; cytokine; experimental study; immune activation; inflammatory milieu; insight; knockout animal; macrophage; mast cell; melanoma; mouse model; new therapeutic target; prevent; public health relevance; tumor; tumor immunology; tumor microenvironment; tumorigenic

 DESCRIPTION (provided by applicant): Allergic contact dermatitis (ACD) is a common skin inflammatory condition with rapidly rising prevalence among industrial nations in recent decades. Acute ACD is characterized by an intense skin rash and itching that develops at the site of exposure to contact allergens like nickel in about 20% of general population. Acute ACD is known to have tumor-suppressing effects in the skin, which has led to its use for the treatment of warts and skin cancers. However, the effects of chronic ACD on skin cancer have not been fully investigated. Implantable medical devices such as orthopedic, dental, and cardiac implants are a source of chronic ACD. These devices are being increasingly used in medical practice, which highlights the importance of research on chronic ACD to better treat this condition and prevent its associated adverse events. In a recent report, we found that chronic ACD to an orthopedic metal implant led to an invasive skin cancer in a patient. To demonstrate a causal relationship, we used the standard mouse model of contact hypersensitivity and showed that chronic application of a contact allergen to carcinogen-treated skin led to the development of aggressive skin cancers in the animals. The chronic ACD-associated inflammation was required for the skin cancer development. Importantly, we found a similar tumor-promoting inflammatory environment surrounding the skin cancer in our patient. These findings highlight a fundamental question: how does an anti-tumor immune response turn into a pro-tumor immune environment in its chronic phase? In order to address this question and determine the mechanism of tumor promotion by chronic ACD, I hypothesized that (a) skin-derived factors mediate the transition from anti-tumor skin inflammation in acute ACD to pro-tumor skin inflammation in chronic ACD, and (b) the tumor-promoting immune environment in chronic ACD is mediated by the interactions between several groups of immune cell types. To test these hypotheses, I propose to (1) determine the mechanism that mediates the transition from tumor-suppressing immune response in acute ACD to tumor- promoting immune environment in chronic ACD, and (2) Determine the mechanism of tumor promotion in chronic ACD. The outcome of this research will provide a mechanistic insight into the role of ACD in skin cancer development. Considering the role of chronic inflammation in promoting cancer development in several organs, the understanding of how chronic ACD promotes skin cancer will be highly applicable in blocking the tumor-promoting effects of chronic inflammation in the skin and other organs.

 描述（由适用提供）：过敏性接触性皮炎（ACD）是一种常见的皮肤炎症状况，最近几十年来工业国家的患病率迅速上升。急性ACD的特征是严重的皮疹和瘙痒在暴露于接触过敏原的位置，如镍（如镍）约20％。已知急性ACD在皮肤中具有肿瘤抑制作用，这导致其用于治疗疣和皮肤癌。但是，尚未对慢性ACD对皮肤癌的影响进行全面研究。可植入的医疗设备，例如骨科，牙科和心脏不安是慢性ACD的来源。这些设备越来越多地用于医学实践，这突出了对慢性ACD的研究的重要性，以更好地治疗这种情况并防止其相关的不良事件。在最近的一份报告中，我们发现对骨科金属植入物的慢性ACD导致患者的侵入性皮肤癌。为了证明因果关系，我们使用了接触超敏反应的标准小鼠模型，并表明将接触过敏原的长期应用在致癌物处理的皮肤上导致动物中侵袭性皮肤癌的发展。皮肤癌发展需要长期与ACD相关的感染。重要的是，我们发现患者皮肤癌周围具有类似的肿瘤炎症环境。这些发现突出了一个基本的问题：抗肿瘤免疫增强响应如何在其慢性阶段变成亲肿瘤的免疫环境？为了解决这个问题并确定慢性ACD促进肿瘤的机制，我假设（a）皮肤衍生的因子介导了从急性ACD中抗肿瘤皮肤感染到慢性ACD中肿瘤皮肤感染的过渡，（b）在慢性ACD中培养了肿瘤的免疫环境，是通过慢性ACD进行了多个型组中的几个相互作用。为了检验这些假设，我建议（1）确定介导从急性ACD中的肿瘤抑制免疫环境转变为慢性ACD中肿瘤促进免疫环境的过渡，（2）确定慢性ACD中Tumor促进的机制。这项研究的结果将提供对ACD在皮肤癌发展中的作用的机械见解。考虑到慢性感染在促进多个器官癌症发展中的作用，对慢性ACD促进皮肤癌的理解将在阻断皮肤和其他器官中慢性感染的肿瘤促进作用方面非常适用。