The Role of Allergic Contact Dermatitis in Skin Carcinogenesis

 描述（由申请人提供）：过敏性接触性皮炎（ACD）是一种常见的皮肤炎性疾病，近几十年来在工业化国家的发病率迅速上升。急性ACD的特征是在约20%的普通人群中暴露于镍等接触性过敏原的部位出现强烈的皮疹和瘙痒。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。然而，慢性ACD对皮肤癌的影响尚未得到充分研究。植入式医疗器械，如骨科、牙科和心脏植入物是慢性ACD的来源。这些设备越来越多地用于医疗实践，这突出了对慢性ACD进行研究以更好地治疗这种疾病并预防其相关不良事件的重要性。在最近的一份报告中，我们发现骨科金属植入物的慢性ACD导致患者发生浸润性皮肤癌。为了证明因果关系，我们使用了接触性超敏反应的标准小鼠模型，并表明长期将接触性过敏原应用于致癌物处理的皮肤会导致动物发生侵袭性皮肤癌。慢性ACD相关炎症是皮肤癌发展所必需的。重要的是，我们在患者的皮肤癌周围发现了类似的促肿瘤炎症环境。这些发现突出了一个基本问题：抗肿瘤免疫反应如何在慢性阶段转变为促肿瘤免疫环境？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）皮肤衍生因子介导急性ACD中的抗肿瘤皮肤炎症向慢性ACD中的促肿瘤皮肤炎症的转变，以及（B）慢性ACD中的促肿瘤免疫环境由几组免疫细胞类型之间的相互作用介导。为了验证这些假设，我建议（1）确定介导从急性ACD中的肿瘤抑制免疫应答向慢性ACD中的肿瘤促进免疫环境转变的机制，以及（2）确定慢性ACD中的肿瘤促进机制。这项研究的结果将为ACD在皮肤癌发展中的作用提供一个机制性的见解。考虑到慢性炎症在促进几个器官中的癌症发展中的作用，了解慢性ACD如何促进皮肤癌将非常适用于阻断皮肤和其他器官中慢性炎症的肿瘤促进作用。

 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.