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

1项目概要/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.嗜铬细胞瘤的基因组特征。我的博士后研究与WK拉斯梅尔博士在 4范德比尔特大学重点研究表观遗传因素在肾癌发生发展中的作用。 5职业目标和目的：我的职业目标是成为一个独立的，终身教职的教师在一个高素质的 6研究机构，与跨学科团队合作，专注于寻找肾癌的新疗法。 7职业发展和培训活动：我的培训计划围绕指导，教学培训， 8保护研究时间，以支持我过渡到独立。WK拉斯梅尔博士将担任我的主要导师;她 9将培训我在实验室和人事管理，赠款管理，转化肾癌研究。博士 10 Jeff拉斯梅尔将提供肿瘤微环境方面的指导，Gyan Bhanot博士将提供 11计算生物学我将参加选定的研讨会和讲习班，并继续在研究培训负责任的行为。 12意义与创新：尽管免疫检查点封锁（ICB）在治疗方面取得了显着成功 13例转移性肾癌（RCC），并非所有患者均对治疗有反应。我们最近报道， 14内源性逆转录病毒，一类转座因子（TE），发生在RCC肿瘤的一个子集，可以预测反应 15至RCC中的ICB。作为移动的基因组元件，TE通常被许多表观遗传机制抑制。异常 TE的表达可以激活宿主的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，其导致免疫原性增加，特征在于免疫浸润增加。因此，我们的前提是， TE表达的调节代表了一种新的治疗策略，以增强RCC和其他癌症中对ICB的反应。 19方法：基于迄今为止的证据，我假设1）TE的表观遗传激活增强了新抗原的产生， 20有助于RCC中的免疫原性，和2）存在调节TE活性的另外的表观遗传机制， 这些可以被操纵以促进免疫原性。 22具体目标1：定义转座因子的表观遗传激活在新表位产生中的作用。1A） 23询问与TE的表观遗传激活相关的转录景观。1B）识别自然加工的TE- 24个相关新表位。 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介导TE抑制。2B）确定TE的表观遗传活化如何介导宿主抗病毒应答。2C）阐明 TE诱导的IFN信号传导背后的27种机制。 28过渡到独立：我将在指导阶段申请教师职位，并接受终身教职 第29章过渡到独立阶段我的目标是描述TE相关抗肿瘤的新机制 30免疫和鉴定调节TE的新靶点。这些研究将作为NCI R 01应用的基础。

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.