THE MECHANISM OF TSLP ANTI-TUMOR EFFECTS IN THE SKIN

 描述(申请人提供)：随着美国人口老龄化，癌症的患病率及其对寿命、生活质量和医疗费用的影响正在上升。尽管癌症治疗在过去几十年里有了很大的改善，但它们仍然不足以治疗许多形式的癌症，这表明迫切需要新的方法。一个快速增长的研究领域，有可能极大地改善癌症治疗，那就是使用免疫系统作为抗肿瘤药物。目前，已经开发了几种针对免疫系统的药物来治疗癌症；然而，这些药物主要是为了对抗癌症的晚期，当时癌细胞已经扩散到身体的其他部位。这些药物的有限成功突显了使用免疫系统治疗癌症的根本新方法的必要性。这项应用的目标是探索一种名为胸腺基质淋巴生成素(TSLP)的免疫因子的抗肿瘤特性，这种免疫因子可以驱动高度的免疫激活，足以从一开始就防止癌前病变的癌症形成。这项研究为发现TSLP抗肿瘤作用的免疫机制提供了一个很好的机会，可用于癌症的治疗和预防。为了实现这一目标，我将把皮肤癌作为一种理想的癌症模型来研究，在这种模型中，炎症和癌症发展之间的时空关系可以非常精确地确定。此外，皮肤癌是最常见的癌症类型；它很容易识别，并且可以接受治疗。以改善癌症治疗为最终目标，我计划研究TSLP激活免疫的潜在机制，并确定其对皮肤癌患者治疗的影响。TSLP是在皮肤中产生的，在引起湿疹等过敏性疾病方面发挥着关键作用。我们和其他人已经证明，高水平的TSLP引起的皮疹会导致受影响皮肤对癌症的强烈抵抗力。我们的发现得到了人群研究的支持，这些研究表明，患有过敏性疾病的患者对皮肤癌具有抵抗力。重要的是，我们发现，TSLP水平的短期增加会导致对皮肤癌的长期抵抗，而没有过敏性皮肤病的迹象 在我们的动物模型和病人身上。这一数据提供了证据，表明导致炎症性疾病的免疫因素可以优化用于癌症治疗，同时避免其慢性副作用。为了确定TSLP是否适合用于皮肤癌免疫治疗，我将研究TSLP如何导致皮肤癌耐药。具体地说，这项应用将应用皮肤癌的小鼠模型和临床试验的数据来确定(1)TSLP刺激的免疫细胞检测到的肿瘤相关信号，以特定靶向肿瘤，(2)TSLP激活的免疫细胞抑制皮肤癌发展的下游机制，以及(3)TSLP诱导对人类癌症前病变的影响。这些研究结果将有助于阐明TSLP的抗癌作用机制，并促进其在皮肤癌免疫治疗方面的发展。考虑到免疫系统在癌症生物学中的重要性，了解促炎因子如何影响癌症的发展，对于确定其他可以在癌症治疗中有效的免疫因子具有很高的应用价值。

 DESCRIPTION (provided by applicant): As the U.S. population ages, the prevalence of cancer and its impact on life span, quality of life, and healthcare costs are on the rise. While cancer treatments have greatly improved over the past several decades, they are still inadequate for many forms of cancers, indicating the urgent need for new approaches. A rapidly growing area of research with the potential to greatly improve cancer therapy is the use of immune system as an anti-tumor agent. Currently, several drugs have been developed that target the immune system to treat cancers; however, these drugs are mainly designed to act against late stages of cancers, when cancer cells have already spread to other parts of the body. The limited success of these drugs highlights the need for a fundamentally new approach to cancer treatment using the immune system. The goal of this application is to explore the anti-tumor properties of an immune factor called thymic stromal lymphopoietin (TSLP) that can drive a high degree of immune activation sufficient to prevent cancer formation from pre-cancerous lesions in the first place. This research raises a great opportunity to discover the immune mechanism mediating the anti-tumor effects of TSLP, which can be leveraged in cancer therapy and prevention. To pursue this goal, I will study skin cancer as an ideal cancer model in which the spatial and temporal relationship between inflammation and cancer development can be determined with exceptional precision. Moreover, skin cancer is the most common type of cancer; it is readily identifiable, and amenable to treatment. With the ultimate goal of improving cancer treatment, I plan to study the underlying mechanism of immune activation by TSLP and determine its impact on skin cancer therapy in patients. TSLP is made in the skin and plays a critical role in causing allergic diseases such as eczema. We and others have demonstrated that the skin rash caused by high TSLP levels leads to strong cancer resistance in the affected skin. Our findings are supported by population studies showing resistance to skin cancers among patients with allergic diseases. Importantly, we have found that a short-term increase in TSLP levels leads to a long-lasting resistance to skin cancer with no sign of allergic skin disease in our animal models and patients. This data provides the evidence that immune factors causing inflammatory diseases can be optimized for use in cancer therapy while avoiding their chronic side effects. To determine if TSLP is a good candidate for use in skin cancer immunotherapy, I will study how TSLP causes skin cancer resistance. Specifically, this application will apply mouse models of skin cancer and data from clinical trials to determine (1) the tumor-associated signals that are detected by TSLP-stimulated immune cells to specifically target the tumors, (2) the downstream mechanism by which TSLP-activated immune cells suppress skin cancer development, and (3) the effects of TSLP induction on pre- cancerous skin lesions in humans. The outcome of these studies will help shed light on the mechanism of TSLP action against cancer and promote its development for skin cancer immunotherapy. Considering the emerging importance of the immune system in cancer biology, the understanding of how a pro-inflammatory factor affects cancer development is highly applicable for identifying other immune factors that can be effective in cancer treatment.