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

• 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
• 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

 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（由申请人提供）：癌症是美国第二大常见死因，导致近四分之一的死亡。激活宿主免疫系统的疗法对多种实体瘤显示出巨大的前景，患者表现出强烈而持久的反应。然而，只有不到一半的患者对这些免疫疗法有反应。我们已经证明，使用DNA甲基转移酶抑制剂（DNMTis）的表观遗传学治疗可以通过激活包括内源性逆转录病毒（ERV）在内的双链RNA来“增强”肿瘤的免疫信号传导，并使肿瘤对免疫治疗敏感。该提案指导阶段的目标是进一步表征 ERV 表观遗传调控，并确定 DNMTi 诱导的肿瘤信号传导至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的表观遗传修饰图； 2) 确定哪些表观遗传修饰药物激活 ERV，3) 表征表观遗传对免疫治疗敏感所需的胞质传感器和细胞因子。在 K99 阶段的生物信息学和免疫学培训的基础上，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，它是细胞对病毒 RNA 的反应的核心。 这种免疫反应。总的来说，这些研究将描述表观遗传学在先天免疫反应中的作用，并确定表观遗传学对免疫治疗敏感的机制。该候选人凯瑟琳·基亚皮内利 (Katherine Chiappinelli) 博士对癌症的表观遗传变化有着长期的兴趣。她的独立学术实验室的主要关注点是癌症免疫信号的表观遗传调控。该 K99/R00 提案旨在补充 Chiappinelli 博士之​​前的研究，并为她提供生物信息学和免疫学方面的额外科学培训，使她能够成为一名成功的独立研究者。此外，该提案还包括详细的职业发展计划和咨询委员会，该委员会将协助 Chiappinelli 博士过渡到成为一名独立研究者。她的咨询委员会成员将为她提供免疫学（Drew Pardoll、Cynthia Zahnow）和生物信息学（Gordon Mills、Ting Wang）方面的科学培训，并为她过渡到独立提供指导（Stephen Baylin、Luis Garza）。这项 K99/R00 提案将为 Chiappinelli 博士提供所需的培训，以扩展她博士后工作的发现，并开始她自己独立且成功的研究实验室。