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、生活质量和医疗保健费用的影响不断上升，尽管癌症治疗在过去几十年中取得了很大进展，但仍存在一些问题。对于许多形式的癌症来说，这仍然不足，这表明迫切需要新的方法，并有可能大大改善癌症治疗，目前有几种药物已被用于治疗癌症。已开发出针对免疫系统的治疗然而，这些药物主要用于对抗晚期癌症，此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凸显了对利用免疫进行癌症治疗的全新方法的需求。该应用的目标是探索一种称为胸腺基质淋巴细胞生成素（TSLP）的免疫因子的抗肿瘤特性，该因子可以驱动高度的免疫激活，足以预防癌前病变形成癌症。这项研究提出了一个这是发现介导 TSLP 抗肿瘤作用的免疫机制的绝佳机会，可用于癌症治疗和预防。为了实现这一目标，我将研究皮肤癌作为理想的癌症模型，其中炎症之间的空间和时间关系。此外，皮肤癌是最常见的癌症类型，并且易于治疗，我计划研究免疫的潜在机制。 TSLP 的激活并确定其对皮肤的影响TSLP 是在皮肤中产生的，在引起湿疹等过敏性疾病中起着关键作用。我们和其他人已经证明，高 TSLP 水平引起的皮疹会导致受影响的皮肤具有很强的抗癌能力。人群研究显示过敏性疾病患者对皮肤癌有抵抗力，重要的是，我们发现短期增加 TSLP 水平可以导致对皮肤癌的长期抵抗力，而没有过敏性皮肤病的迹象。 在我们的动物模型和患者中，这些数据提供了证据，表明引起炎症性疾病的免疫因子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 是否是皮肤癌免疫治疗的良好候选者。研究 TSLP 如何导致皮肤癌抵抗，具体而言，该应用程序将应用皮肤癌小鼠模型和临床试验数据来确定 (1) TSLP 刺激的免疫细胞检测到的相关肿瘤信号，以特异性靶向肿瘤。 ）下游机制TSLP 激活的免疫细胞抑制皮肤癌的发展，以及 (3) TSLP 诱导对人类癌前皮肤病变的影响。这些研究的结果将有助于阐明 TSLP 对抗癌症的作用机制，并促进其发展。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发展非常适用于识别其他可有效治疗癌症的免疫因子。