THE MECHANISM OF TSLP ANTI-TUMOR EFFECTS IN THE SKIN

TSLP 皮肤抗肿瘤作用机制

• 批准号: 9001618
• 负责人: Shadmehr Demehri
• 金额: $ 43.5万
• 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: 2015-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9001618
• 关键词: Actinic keratosis; Adverse effects; Affect; Aftercare; Age; Allergic; Allergic Disease; Allergic inflammation; Animal Model; Animals; Antigens; Area; Atopic Dermatitis; Blood; Body part; CD4 Positive T Lymphocytes; Calcipotriene; Cancer Biology; Cancer Model; Cancerous; Candidate Disease Gene; Cells; Characteristics; Chemicals; Chronic; Clinical Trials; Data; Defect; Development; Diagnostic Neoplasm Staging; Disease; Disease Resistance; Double-Blind Method; Eczema; Effector Cell; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Epithelial; Exanthema; FDA approved; Flow Cytometry; Goals; Health Care Costs; Human; Immune; Immune response; Immune system; Immunohistochemistry; Immunotherapy; Individual; Inflammation; Inflammatory; Laboratory Study; Lesion; Ligand Binding; Ligands; Light; Link; Longevity; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular; Mus; Mutation; Nature; Organ; Outcome; Outcome Study; Participant; Patients; Pharmaceutical Preparations; Play; Population; Population Study; Prevalence; Property; Quality of life; RNA Sequences; Randomized; Recruitment Activity; Research; Resistance; Role; Sampling; Signal Transduction; Site; Skin; Skin Cancer; Skin Carcinogenesis; Solid; Squamous cell carcinoma; T-Lymphocyte; Testing; Therapeutic Uses; Topical application; Tumor Antigens; Tumor Immunity; Tumor Suppression; United States; Validation; antitumor agent; antitumor effect; atopy; base; cancer cell; cancer immunotherapy; cancer prevention; cancer therapy; cancer type; cytotoxic; design; exome; human TSLP protein; immune activation; immune clearance; improved; in vitro Assay; innovation; mouse model; neoplastic cell; notch protein; novel; novel strategies; overexpression; prevent; public health relevance; skin cancer prevention; skin disorder; skin lesion; small molecule; success; transcriptome sequencing; tumor

 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.

 描述（由适用提供）：随着美国人口的年龄，癌症的流行及其对寿命，生活质量和医疗保健成本的影响正在上升。虽然在过去的几十年中，癌症治疗却大大改善，但它们仍然对许多形式的癌症仍然不足，表明迫切需要采用新方法。一个快速增长的研究领域，有可能改善癌症治疗的可能性是将免疫系统用作抗肿瘤剂。目前，已经开发出几种针对免疫系统来治疗癌症的药物。但是，当癌细胞已经扩散到人体的其他部位时，这些药物主要设计为对癌症的晚期作用。这些药物的成功有限，凸显了使用免疫系统对癌症治疗的根本新方法的必要性。该应用的目的是探索称为胸腺基质淋巴细胞蛋白（TSLP）的免疫因子的抗肿瘤特性，该因素可以驱动足以防止癌前病变癌症形成的高度免疫活化。这项研究为发现介导TSLP的抗肿瘤作用的免疫力学提供了一个很好的机会，TSLP可以利用癌症治疗和预防。为了实现这一目标，我将研究皮肤癌作为理想的癌症模型，在这种模型中，炎症与癌症发育之间的空间和临时关系可以以非凡的精度确定。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。以改善癌症治疗的最终目的，我计划研究TSLP免疫激活的潜在机制，并确定其对患者皮肤癌治疗的影响。 TSLP是在皮肤中制成的，在引起过敏性疾病（如湿疹）方面起着至关重要的作用。我们和其他人证明，高TSLP水平引起的皮疹会导致受影响的皮肤抗癌的强烈。我们的发现得到了人群研究的支持，表明过敏性疾病患者对皮肤癌的抗性。重要的是，我们发现TSLP水平的短期增加导致对皮肤癌的持久性，没有过敏性皮肤病的迹象 在我们的动物模型和患者中。该数据提供了一个证据，表明引起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是否是用于皮肤癌免疫疗法的良好候选者，我将研究TSLP如何引起皮肤癌耐药性。具体而言，该应用将应用皮肤癌的小鼠模型和临床试验的数据，以确定（1）与肿瘤相关的。 TSLP刺激的免疫细胞检测到特异性靶向肿瘤的信号，（2）TSLP激活的免疫电池细胞抑制皮肤癌的发展，以及（3）TSLP诱导对人类前癌前皮细胞的影响。这些研究的结果将有助于阐明TSLP对癌症作用的机制，并促进其对皮肤癌免疫疗法的发展。考虑到免疫细胞系统在癌症生物学中的出现重要性，对促炎性因素如何影响癌症发展的理解非常适用于确定可以有效治疗癌症治疗的其他免疫因素。