Epigenetic activation of the interferon response to sensitize cancers to immune therapy

干扰素反应的表观遗传激活使癌症对免疫治疗敏感

基本信息

批准号：
9404639
负责人：
Katherine B Chiappinelli
金额：
$ 24.9万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9404639
关键词：
ADAR1 Advisory Committees Affect Azacitidine Binding Bioinformatics Biological CD3 Antigens CRISPR/Cas technology CTLA4 gene Cancer Etiology Cancer cell line Cell Line Cells Cessation of life ChIP-seq Complement DNA Methylation DNA Methyltransferase Inhibitor DNA Sequence DRADA2b protein Data Derivation procedure Development Plans Dose Double-Stranded RNA Endogenous Retroviruses Enzymes Epigenetic Process Exhibits Family Genes Genomics Goals Histone Deacetylase Immune Immune response Immune signaling Immune system Immunology Immunotherapy Innate Immune Response Interferon Activation Interferon Type I Interferon-alpha Interferons KDM1A gene KDM5B gene Knock-out Laboratories Laboratory Research Malignant Neoplasms Maps Melanoma Cell Mentors Methylation Modification Mus Mutate Pathway interactions Patients Pharmacotherapy Phase Physiological Play Primary Neoplasm Protein p53 RANTES RNA RNA Editing Recruitment Activity Repetitive Sequence Reporter Research Research Personnel Role Sampling Short Interspersed Nucleotide Elements Signal Transduction Solid Neoplasm T-Lymphocyte TBK1 gene TLR3 gene TP53 gene Training Transcriptional Regulation Tumor Burden United States Untranslated RNA Up-Regulation Viral Work cancer cell cancer therapy career development checkpoint therapy combinatorial cytokine design epigenetic drug epigenetic regulation experimental study genome sequencing genome wide methylation histone modification immune activation immune checkpoint inhibitor/antagonist innovation insight interest knock-down melanoma member mortality mouse model mutant neoplastic cell novel ovarian neoplasm overexpression public health relevance response sensor targeted treatment transcriptome sequencing tumor tumorigenesis viral RNA whole genome

项目摘要

DESCRIPTION (provided by applicant): Cancer is the second most common cause of mortality in the United States, causing nearly one out of four deaths. Therapies that activate the host immune system have shown tremendous promise for a wide variety of solid tumors, with patients exhibiting vigorous and durable responses. However, fewer than half of patients respond to these immune therapies. We have shown that epigenetic therapy using DNA methyltransferase inhibitors (DNMTis) can "boost" immune signaling from tumors, through activation of double-stranded RNA including endogenous retroviruses (ERVs), and sensitize tumors to immune therapy. The goals of the mentored phase of this proposal are to further characterize ERV epigenetic regulation and determine the exact mechanism of DNMTi-induced tumor signaling to the host immune system. During the K99 phase, I will 1) use whole-genome sequencing to map epigenetic modifications at ERVs; 2) determine which epigenetic modifying drugs activate ERVs, and 3) characterize cytosolic sensors and cytokines necessary for epigenetic sensitization to immune therapy. Building on the bioinformatics and immunology training from the K99 phase, the goal of the R00 phase is to expand the genomic analysis to investigate other dsRNAs that may contribute to the DNMTi-induced immune response. In addition, I will examine the role of RNA editing, central to the cellular response to viral RNA, in this immune response. Overall, these studies will characterize the role of epigenetics in the innate immune response and determine the mechanism(s) for epigenetic sensitization to immune therapy. The candidate, Dr. Katherine Chiappinelli, has a longstanding interest in epigenetic changes in cancer. The main focus of her independent academic laboratory will be epigenetic regulation of immune signaling in cancer. This K99/R00 proposal is designed to complement Dr. Chiappinelli's previous research and provide her with additional scientific training in bioinformatics and immunology to allow her to succeed as an independent investigator. In addition, this proposal includes a detailed career development plan and an advisory committee that will assist Dr. Chiappinelli through the transition to becoming an independent investigator. Members of her advisory committee will provide her with scientific training in immunology (Drew Pardoll, Cynthia Zahnow) and bioinformatics (Gordon Mills, Ting Wang) as well as guidance as she transitions to independence (Stephen Baylin, Luis Garza). This K99/R00 proposal will provide Dr. Chiappinelli with the training needed to extend the findings from her postdoctoral work and begin her own independent and successful research laboratory.

描述（由适用提供）：癌症是美国第二大死亡率的原因，造成四分之一死亡中的癌症。激活宿主免疫系统的疗法对各种实体瘤表现出了巨大的希望，患者表现出剧烈耐用的反应。但是，不到一半的患者对这些免疫疗法有反应。我们已经表明，使用DNA甲基转移酶抑制剂（DNMTIS）的表观遗传疗法可以通过激活包括内源性逆转录病毒（ERV）的双链RNA来“增强”肿瘤的免疫信号，而对免疫疗法进行敏感肿瘤。该提案的修补阶段的目标是进一步表征ERV表观遗传调节，并确定DNMTI-I诱导的肿瘤信号传导对宿主免疫系统的确切机制。在K99阶段，我将1）使用全基因组测序来绘制ERV的表观遗传修饰； 2）确定哪些表观遗传修饰药物激活ERV，3）表征对免疫疗法的表观遗传敏感性所需的胞质传感器和细胞因子。基于K99阶段的生物信息学和免疫学培训，R00阶段的目标是扩展基因组分析，以研究可能有助于DNMTI诱导的免疫反应的其他DSRNA。此外，我将研究RNA编辑的作用，这是细胞对病毒RNA的核心，在这种免疫响应。总体而言，这些研究将表征表观遗传学在先天免疫响应中的作用，并确定对免疫治疗的表观遗传学敏感性的机制。候选人Katherine Chiappinelli博士对癌症的表观遗传变化有很长的兴趣。她独立的学术实验室的主要重点是对癌症免疫信号的表观遗传调节。该K99/R00提案旨在完成Chiappinelli博士以前的研究，并为她提供了在生物信息学和免疫学方面的其他科学培训，以使她能够成功成为独立研究者。此外，该提案还包括一个详细的职业发展计划和一个咨询委员会，该委员会将通过过渡到成为独立调查员，以帮助Chiappinelli博士。她的咨询委员会的成员将为她提供免疫学科学培训（Drew Pardoll，Cynthia Zahnow）和生物信息学（Gordon Mills，Ting Wang），以及她向独立过渡（Stephen Baylin，Luis Garza）。该K99/R00提案将为Chiappinelli博士提供扩展其博士后工作的发现所需的培训，并开始自己的独立和成功的研究实验室。