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Activation of transposable elements as an endogenous source of neoepitopes and mediators of tumor immunogenicity

转座元件的激活作为新表位的内源性来源和肿瘤免疫原性的介质

基本信息

批准号：
10663369
负责人：
Aguirre A de Cubas
金额：
$ 11.98万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663369
关键词：
Antigen Presentation Antiviral Response Binding Bioinformatics Caliber Cell Line Cell physiology Clear cell renal cell carcinoma Clinical Clinical Trials Computational Biology DNA DNA Transposable Elements Data Dedications Development Disease Doctor of Philosophy Educational workshop Elements Endogenous Retroviruses Epigenetic Process Event Faculty Fluorescence Microscopy Future Genetic Transcription Genomics Goals Grant Immune response Immune system Immunity Immunologics Immunology Immunooncology Immunoprecipitation Immunosuppression Immunotherapy Impotence Institution Interferon Activation Interferons Investigation Laboratories Libraries Malignant Neoplasms Mass Spectrum Analysis Mediating Mediator Mentored Research Scientist Development Award Mentors Mentorship Messenger RNA Open Reading Frames Pathogenicity Pathway interactions Patients Peptides Personnel Management Pharmaceutical Preparations Pharmacotherapy Phase Pheochromocytoma Positioning Attribute Postdoctoral Fellow Process Production Prognosis Proteins Proteomics RNA RNA Splicing Regulation Relapse Renal Cell Carcinoma Renal carcinoma Reporter Reporting Repression Research Research Personnel Research Training Response Elements Role Signal Transduction Source T-Lymphocyte TBK1 gene Testing Therapeutic Time Training Training Activity Transcript Transcription Initiation Site Translating Universities Viral anti-CTLA4 anti-PD-L1 anti-cancer anticancer research cancer therapy career career development chromatin immunoprecipitation clinical application design epigenetic therapy evidence base experience genomic data high throughput screening immune activation immune cell infiltrate immune checkpoint blockade immune clearance immunogenic immunogenicity in vivo Model innovation insight knock-down member neoantigens new therapeutic target next generation sequencing novel novel therapeutic intervention novel therapeutics outcome prediction pathogen patient population predicting response protein aminoacid sequence receptor research study response success tenure track translational cancer research tumor tumor immunology tumor microenvironment tumor-immune system interactions urologic

项目摘要

1 PROJECT SUMMARY/ABSTRACT 2 Candidate Background: I received my Ph.D. from the Autonomous University of Madrid with Dr. Mercedes Robledo, 3 focusing on genomic characterization of pheochromocytoma. My postdoctoral research studies with Dr. WK Rathmell at 4 Vanderbilt University with a focus epigenetic factors in the development and progression of renal cancer. 5 Career Goals and Objectives: My career goal is to become an independent, tenure-track faculty member at a high-caliber 6 research institution, working with an interdisciplinary team, and focusing on identifying new therapies for kidney cancer. 7 Career Development and Training Activities: My training plan revolves around mentorship, didactic training, and 8 protected research time to support my transition to independence. Dr. WK Rathmell will serve as my primary mentor; she 9 will train me in laboratory and personnel management, grant administration, and translational kidney cancer research. Dr. 10 Jeff Rathmell will provide mentorship in tumor microenvironment, and Dr. Gyan Bhanot will provide mentorship in 11 computational biology. I will attend selected seminars and workshops, and continue responsible conduct in research training. 12 Significance and Innovation: Although immune checkpoint blockade (ICB) has shown remarkable success in treating 13 metastatic kidney cancer (RCC), not all patients respond to therapy. We recently reported that high expression of 14 endogenous retroviruses, a class of transposable element (TE), occurs in a subset of RCC tumors and can predict response 15 to ICB in RCC. Mobile genomic elements, TEs are usually suppressed by a number of epigenetic mechanisms. Aberrant 16 expression of TEs can activate host antiviral responses and produce neoantigens, and in some RCCs, activate antiviral response 17 that results in increased immunogenicity, characterized by increased immune infiltrate. Thus, it is our premise that epigenetic 18 modulation of TE expression represents a novel therapeutic strategy to enhance response to ICB in RCC and other cancers. 19 Approach: Based evidence to date, I hypothesize 1) that epigenetic activation of TEs enhances neoantigen production to 20 contribute to immunogenicity in RCC, and 2) that additional epigenetic mechanisms exist that regulate TE activity and that 21 these can be manipulated to promote immunogenicity. 22 Specific Aim 1: Define the role that epigenetic activation of transposable elements has in neoepitope production. 1A) 23 Interrogate transcriptional landscapes associated with epigenetic activation of TEs. 1B) Identify naturally processed TE- 24 associated neoepitopes. 25 Specific Aim 2: Define additional epigenetic mechanisms governing TE expression. 2A) Define epigenetic mechanisms 26 mediating TE suppression. 2B) Determine how epigenetic activation of TEs mediate host antiviral response. 2C) Elucidate 27 mechanisms behind TE-induced IFN signaling. 28 Transition to Independence: I will apply to faculty positions during the Mentored phase and accepting a tenure track 29 position to transition to the Independent phase. My goal is to characterize novel mechanisms for TE-associated antitumor 30 immunity and identify novel targets regulating TEs. These studies will serve as the basis for an NCI R01 application.

1 项目摘要/摘要 2 候选人背景：我获得了博士学位。来自马德里自治大学的 Mercedes Robledo 博士， 3 专注于嗜铬细胞瘤的基因组特征。我在 WK Rathmell 博士的指导下进行博士后研究 4 范德堡大学，重点研究肾癌发生和进展中的表观遗传因素。 5 职业目标和目标：我的职业目标是成为一名高素质的独立终身教授 6 研究机构，与跨学科团队合作，专注于寻找肾癌新疗法。 7 职业发展和培训活动：我的培训计划围绕指导、教学培训和 8 保护研究时间以支持我向独立过渡。 WK Rathmell 博士将担任我的主要导师；她 9 将在实验室和人事管理、拨款管理和转化肾癌研究方面对我进行培训。博士。 10 Jeff Rathmell 将在肿瘤微环境方面提供指导，Gyan Bhanot 博士将在肿瘤微环境方面提供指导 11 计算生物学。我将参加选定的研讨会和讲习班，并继续负责任地进行研究培训。 12 意义和创新：尽管免疫检查点阻断 (ICB) 在治疗方面取得了显着的成功 13 转移性肾癌 (RCC)，并非所有患者都对治疗有反应。我们最近报道了高表达 14 内源性逆转录病毒是一类转座元件 (TE)，存在于 RCC 肿瘤的子集中，可以预测反应 15 路至 RCC 的 ICB。可移动基因组元件 TE 通常受到多种表观遗传机制的抑制。异常 16 TE 的表达可以激活宿主抗病毒反应并产生新抗原，并且在一些 RCC 中激活抗病毒反应 17 导致免疫原性增加，其特征是免疫渗透增加。因此，我们的前提是表观遗传 18 TE 表达的调节代表了一种新的治疗策略，可增强 RCC 和其他癌症对 ICB 的反应。 19 方法：根据迄今为止的证据，我假设 1) TE 的表观遗传激活可增强新抗原的产生，从而 20 有助于 RCC 的免疫原性，2) 存在调节 TE 活性的其他表观遗传机制，并且 21 这些可以被操纵以促进免疫原性。 22 具体目标 1：定义转座元件的表观遗传激活在新表位产生中的作用。 1A) 23 询问与 TE 表观遗传激活相关的转录景观。 1B) 识别自然加工的 TE- 24 个相关的新表位。 25 具体目标 2：定义控制 TE 表达的其他表观遗传机制。 2A) 定义表观遗传机制 26 调解 TE 抑制。 2B) 确定 TE 的表观遗传激活如何介导宿主抗病毒反应。 2C) 阐明 27 TE 诱导的 IFN 信号转导背后的机制。 28 过渡到独立：我将在指导阶段申请教职并接受终身教职 29 位置过渡到独立阶段。我的目标是表征 TE 相关抗肿瘤的新机制 30 免疫力并确定调节 TE 的新靶点。这些研究将作为 NCI R01 申请的基础。