Epithelium-derived alarmins role in breast cancer immunoprevention

上皮源性警报素在乳腺癌免疫预防中的作用

基本信息

批准号：
10468153
负责人：
Shadmehr Demehri
金额：
$ 80.19万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468153
关键词：
Address Allergic inflammation Animal Model Antigen Presentation Automobile Driving BRCA mutations BRCA1 gene Biological Assay Blocking Antibodies Breast Breast Cancer Model Breast Cancer Prevention Breast Carcinogenesis Breast Epithelial Cells CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cancer Etiology Cells Cessation of life Clinic Clinical Clinical Trials DNA Damage DNA Sequence Alteration Development Disease Disseminated Malignant Neoplasm Double-Blind Method Epithelial Epithelial Cells Foundations Gland Goals Immune Immune response Immune system Immunity Immunologic Factors Immunoprevention Immunotherapeutic agent Immunotherapy In Situ In Vitro Individual Inflammation Interleukins Lead Lesion Malignant - descriptor Malignant Neoplasms Mediating Memory Molecular Nature Outcome Pathway interactions Patients Pattern Phase Premalignant Cell Randomized Recurrence Regulatory T-Lymphocyte Research Resolution Role Shapes Signal Transduction Skin Skin Cancer Stress Surveys T cell response T-Cell Activation T-Lymphocyte TSLP gene Testing Therapeutic Therapeutic Uses Tissues Transgenic Animals Tumor Immunity Tumor Suppression United States Woman adaptive immune response adaptive immunity adenoma advanced disease breast lesion cancer invasiveness cancer prevention combat cytokine cytotoxic effector T cell epidemiology study high risk high risk population immune activation knockout animal malignant breast neoplasm mammary mammary epithelium mutation carrier neoplastic new therapeutic target novel premalignant prevent release factor response skin cancer prevention tumor tumor immunology

项目摘要

Project Summary/Abstract: Advances in cancer immunology has led to the successful use of patients' own immune cells to combat metastatic cancers. However, the therapeutic potential of the immune system in eliminating premalignant cells and preventing their progression to invasive cancers is unclear. To determine the benefit of activating the immune system to prevent cancer development and recurrence, we study the immune pathways that lead to effective immune activation against early phases of breast cancer development. Breast cancer is the most common internal cancer and second cause of cancer deaths among women in the United States. Importantly, the individuals at high risk of developing breast cancer due to underlying genetic mutations and those with premalignant lesions can be clinically identified and treated. Therefore, discovering an effective approach to activate the patients' own immune system against early breast precursor lesions may yield a lasting memory that can prevent breast cancer development and recurrence in this high-risk population. Our previous studies have demonstrated that a skin-derived immune factor called thymic stromal lymphopoietin (TSLP) suppresses the early stages of skin and breast cancer development. We have been able to extend these finding to clinics through a randomized double-blind clinical trial in which we find TSLP induction to promote a robust immune activation against skin cancer precursors and their complete clearance. In order to determine the precise mechanism of TSLP-induced immune response against early premalignant cells in the breast, and to extend our findings to other similar immune factors in high-risk patients, we aim to (1) determine the immune cells and signals that target breast premalignant cells in response to TSLP, (2) investigate the role of other immune factors released by breast cells that can induce immune response to block breast cancer development, and (3) determine the factors that are driving the immune response in the breast glands of patients with genetic mutations and utilize them for induction of an optimal immune response against early breast cancer. The outcomes of the proposed research will establish a foundation for the use of the immune system in blocking breast cancer development and provide novel therapeutic targets for breast cancer immunoprevention.

项目摘要/摘要：癌症免疫学的进步导致成功使用患者自己的免疫细胞来对抗转移性癌症。但是，免疫系统消除预抗细胞的治疗潜力并且不清楚他们的进展到侵入性癌症。确定激活免疫系统可防止癌症发育和复发，我们研究导致的免疫途径对乳腺癌发展的早期阶段的有效免疫激活。乳腺癌是最大的美国妇女中常见的内部癌症和癌症死亡的第二个原因。重要的是，由于基本的基因突变以及患有乳腺癌的高风险的个体可以在临床上识别和治疗前病变。因此，发现一种有效的方法激活患者自己的免疫系统针对早期的乳房前体病变，可能会产生持久的记忆这可以防止这种高危人群的乳腺癌发展和复发。我们以前的研究已经证明了皮肤衍生的免疫因子称为胸腺基质淋巴结蛋白（TSLP）皮肤和乳腺癌发育的早期阶段。我们已经能够将这些发现扩展到诊所通过一项随机双盲临床试验，我们发现TSLP诱导以促进可靠的免疫针对皮肤癌前体的激活及其完全清除率。为了确定精确 TSLP诱导的免疫反应针对乳房中早期预抗细胞的免疫反应，并延伸我们对高危患者其他类似免疫因子的发现，我们的目标是（1）确定免疫细胞和信号表明靶向乳房预抗响应TSLP的信号，（2）研究其他免疫的作用乳腺细胞释放的因素可以诱导免疫反应以阻断乳腺癌的发展，（3）确定遗传患者乳腺中驱动免疫反应的因素突变并利用它们来诱导针对早期乳腺癌的最佳免疫反应。这拟议研究的结果将为使用免疫系统阻止的基础建立基础乳腺癌的发展并为乳腺癌免疫预防提供新的治疗靶标。