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

1 .项目摘要/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.