Inhibition of DNA methylation to prevent tumor-induced immune tolerance

抑制DNA甲基化以防止肿瘤诱导的免疫耐受

• 批准号: 8091764
• 负责人: CHRISTOPHER J GAMPER
• 金额: $ 13.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091764
• 关键词: Antigens; Bioinformatics; Biology; Biotechnology; Cancer Vaccines; Cell Cycle; Chromatin; Collaborations; Complement; Cyclin A; Cytokine Gene; DNA Methylation; DNA Methylation Inhibition; DNA Methyltransferase; DNA Modification Methylases; DNA Sequence; DNA Sequence Rearrangement; Data; Education; Educational Curriculum; Elements; Environment; Epigenetic Process; Exposure to; Foundations; Gene Expression; Gene Silencing; Genes; Genomics; Goals; Immune Tolerance; Immune response; Immunology; Immunotherapy; Interferons; Interruption; Laboratories; Lead; Lymphocyte; Lymphoma; Malignant Neoplasms; Measurement; Measures; Mediating; Mentors; Mentorship; Methylation; Modeling; Mus; Patients; Pattern; Pediatric Oncology; Phenotype; Physicians; Play; Postdoctoral Fellow; Publishing; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Research; Research Personnel; Resistance; Role; Scientist; Solid; T-Cell Activation; T-Lymphocyte; Testing; Time; Translating; Tumor Antigens; Tumor Immunity; Universities; Vaccines; abstracting; anergy; base; bisulfite; cancer therapy; career; clinically relevant; cytokine; daughter cell; genome-wide; graduate student; in vivo; inhibitor/antagonist; instructor; medical schools; mouse model; next generation; novel; novel strategies; prevent; promoter; response; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): Project Summary/Abstract Candidate I am a second year Instructor in the Division of Pediatric Oncology at the Johns Hopkins University School of Medicine. In this proposal I aim to complement ongoing research in immunology with a formal bioinformatics education to permit me to analyze genome-wide patterns of DNA methylation in lymphocytes, in particular in T cells that have been activated by tumor antigen. My immediate goals are to test the hypothesis that DNA methylation and silencing of T cell activation genes contributes to the ineffective immune responses against cancer. My long-term goal is to utilize this proposal to establish an independent line of research that may be translated into clinically relevant immunotherapy for patients in the Division of Pediatric Oncology. Research My prior efforts have identified a critical role for DNA Methyltransferase 3a (DNMT3a) in catalyzing de novo DNA methylation of cytokine genes in T cells following activation. In this proposal I will test the hypothesis that such methylation contributes to ineffective anti-tumor immunity. I will use a robust model of mice whose T cells lack DNMT3a to identify unappreciated targets of DNA methylation by comparing tumor exposed and activated T cells in an genome-wide methylation analysis. I will determine whether lack of such methylation underlies the observed ability of DNMT3a KO T cells to better reject tumors, and I will test whether treatment DNMT inhibitors can achieve a similar effect. Such a finding would identify DNMT inhibition as a novel means of enhancing anti-tumor immunity and potentially lead to more effective cancer vaccine strategies. Environment: My proposal will be carried out under the ongoing mentorship of Dr. Jonathan Powell, a leading researcher in the biology of T cell activation, effector differentiation, and tolerance. He leads a highly productive laboratory and has successfully mentored four graduate students and three postdoctoral fellows. Through collaboration with Dr. Srinivasan Yegnasubramanian, Director of the Next Generation Sequencing Center, I will apply the latest technological advances in next generation sequencing to the measurement of global patterns of genomic DNA methylation. The Center for Biotechnology Education and the Center for Computational Genomics will provide a curriculum for formal education in bioinformatics. These elements combine to provide me with a solid foundation to develop a career as an independent physician-scientist. PUBLIC HEALTH RELEVANCE: Project Narrative We propose that tumors bypass and suppress T cell immune responses by turning off genes within T cells using a process called DNA methylation. This project seeks to identify T cell genes turned off by tumors due to DNA methylation and test whether blocking DNA methylation is able to enhance immune responses against tumors. Identifying a role for DNA methylation in preventing anti-tumor immunity suggests that drugs that block DNA methylation will enhance treatment of cancer with immunotherapy.

描述(由申请人提供)：项目摘要/摘要候选人我是约翰·霍普金斯大学医学院儿科肿瘤科的二年级讲师。在这项提议中，我的目标是用正规的生物信息学教育来补充正在进行的免疫学研究，使我能够分析淋巴细胞中DNA甲基化的全基因组模式，特别是在被肿瘤抗原激活的T细胞中。我的直接目标是验证这样一个假设，即DNA甲基化和T细胞激活基因的沉默导致了对癌症的无效免疫反应。我的长期目标是利用这一提议建立一条独立的研究路线，可以转化为儿科肿瘤科患者的临床相关免疫疗法。我之前的研究发现，DNA甲基转移酶3a(DNMT3a)在T细胞激活后催化细胞因子基因从头DNA甲基化中起着关键作用。在这项提议中，我将检验这样一种假设，即这种甲基化有助于无效的抗肿瘤免疫。我将使用一个T细胞缺乏DNMT3a的小鼠的强大模型，通过在全基因组甲基化分析中比较暴露于肿瘤和激活的T细胞来识别DNA甲基化的未知目标。我将确定是否缺乏这种甲基化是DNMT3a KO T细胞更好地排斥肿瘤的观察能力的基础，我将测试治疗DNMT抑制剂是否可以达到类似的效果。这一发现将确定DNMT抑制是一种增强抗肿瘤免疫的新方法，并有可能导致更有效的癌症疫苗策略。环境：我的建议将在乔纳森·鲍威尔博士的持续指导下进行，他是T细胞激活、效应器分化和耐受生物学方面的领先研究员。他领导着一个高生产率的实验室，并成功地指导了四名研究生和三名博士后研究员。通过与下一代测序中心主任斯里尼瓦桑·耶格纳苏布拉曼尼亚博士的合作，我将把下一代测序的最新技术进步应用到基因组DNA甲基化的全球模式的测量中。生物技术教育中心和计算基因组学中心将为生物信息学的正规教育提供课程。这些因素结合在一起，为我发展成为一名独立的内科科学家提供了坚实的基础。 公共卫生相关性：项目叙述我们建议肿瘤通过关闭T细胞内的基因来绕过并抑制T细胞免疫反应，这一过程被称为DNA甲基化。该项目旨在识别由于DNA甲基化而导致肿瘤关闭的T细胞基因，并测试阻断DNA甲基化是否能够增强对肿瘤的免疫反应。确定DNA甲基化在预防抗肿瘤免疫中的作用表明，阻止DNA甲基化的药物将通过免疫疗法加强癌症的治疗。