Characterization of tumor-specific human endogenous retroviruses in clear cell Renal Cell Carcinoma

/ ABSTRACT Human endogenous retroviruses (HERVs) comprise roughly 8% of our genome. Originally considered “junk DNA”, we now know that HERVs play diverse roles relating to human health, innate immunity, and cancer. Repetitive elements have been notoriously difficult to study and quantify due to their repetitive nature and the lack of a standardized database. In this project, I will leverage a comprehensive database of HERV loci (HERVdb) created in the Blanco-Melo Lab to accurately measure the expression of HERVs and investigate their role in clear cell renal cell carcinoma (ccRCC), a common and aggressive form of kidney cancer that accounts for 80% of renal cancer cases. HERV expression in ccRCC has been linked to tumor immunogenicity and response to immunotherapy, making it a promising area of research. Our hypothesis is that HERVs are abnormally transcriptionally activated in tumor cells, where they are recognized by the immune system due to absence of expression in normal cells; HERV products (RNA or protein) can thus prime the anti-tumor immune response, resulting in a HERV specific immune response. To test this, I will pursue two main aims: Aim 1: Define the unique signature of HERVs in ccRCC (clear cell Renal Cell Carcinoma). Aim 2: Explore the role of HERV-derived tumor-associated antigens across ccRCC samples. The goal is to establish a clear baseline of HERV expression in ccRCC, identify tumor-specific HERVs, and explore relevant HERV-derived peptides that could serve as potential therapeutic targets. Ultimately, this project aims to demonstrate that HERVdb can be used to identify HERVs as targets for ccRCC treatments, and to establish a reproducible workflow for the interrogation of HERVs in other cancers. Project Number: 1F31CA306243-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Sophia Kogut | Institution: FRED HUTCHINSON CANCER CENTER, SEATTLE, WA | Award Amount: $46,368 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F09A-R (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11244656