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

1.项目摘要/摘要 候选人背景：我在马德里自治大学获得博士学位，师从梅赛德斯·罗布莱多博士， 3.关注嗜铬细胞瘤的基因组特征。我在WK Rathmell博士那里学习的博士后研究 范德比尔特大学重点研究了表观遗传因素在肾癌发生发展中的作用。 5.职业目标和目标：我的职业目标是成为一名独立的、终身教职的高素质教师 6研究机构，与跨学科团队合作，专注于寻找肾癌的新疗法。 职业发展和培训活动：我的培训计划围绕导师、授课培训和 8个受保护的研究时间，以支持我向独立的过渡。WK Rathmell博士将担任我的主要导师；她 我将在实验室和人事管理、赠款管理和肾癌翻译研究方面对我进行培训。Dr。 Jeff Rathmell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工作坊，并继续进行负责任的研究培训。 12.意义和创新：尽管免疫检查点阻断(ICB)在治疗中显示出显著的成功 13对于转移性肾癌(RCC)，并不是所有的患者都对治疗有反应。我们最近报道了高表达的 内源性逆转录病毒是一类转座元件(TE)，存在于肾细胞癌的一个亚群中，并可预测疗效 15%给RCC的ICB。可移动的基因组元件，TES通常被一些表观遗传机制抑制。反常的 TES的表达可以激活宿主的抗病毒反应，并产生新的抗原，在某些RCC中，还可以激活抗病毒反应 17.这会导致免疫原性增强，其特征是免疫渗入增加。因此，我们的前提是表观遗传学 18调节TE的表达代表了一种新的治疗策略，以增强肾癌和其他癌症对ICB的反应。 方法：基于到目前为止的证据，我假设1)TES的表观遗传激活促进了新抗原的产生 20有助于肾癌的免疫原性，以及2)存在调节TE活性的额外表观遗传机制，以及 其中21种可以被操纵以提高免疫原性。 22具体目标1：确定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TES的表观遗传激活相关的转录景观。1b)识别自然加工的TE- 24个相关的新表位。 25.具体目标2：确定管理TE表达的其他表观遗传机制。2a)定义表观遗传机制 26.调停TE镇压。2b)确定TES的表观遗传激活如何介导宿主抗病毒反应。2C)澄清 27 TE诱导干扰素信号转导的机制。 28.向独立的过渡：我将在指导阶段申请教职，并接受终身教职 29过渡到独立阶段的立场。我的目标是描述TE相关抗肿瘤的新机制 30提高免疫力，并确定监管TES的新目标。这些研究将作为NCI R01申请的基础。

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.