Abstract 2329: Understanding epigenetic-driven transposable re-expression and its impact on immune activation in the serrated pathway of colorectal tumorigenesis

Abstract An active immune system plays a central role in preventing the progression from precancerous lesions to invasive cancers. Identifying the molecular markers that dictate effective immune surveillance is essential for advancing cancer prevention strategies. A higher level of immune cell infiltration is observed in serrated lesions, a subtype of colorectal premalignant lesions, in comparison to the other common subtype, conventional adenoma. However, the mechanism underlying the elevated immune response in serrated lesions remains poorly understood because hypermutation, which is considered as the source of immunogenicity conventionally, is absent in serrated lesions. One alternative source of immunogenicity can be transposable elements (TEs), which are mobile DNA sequences typically epigenetically silenced in mature tissues but expressed in fetal developmental stage and cancers. We hypothesize that aberrant expression of TEs drives immune activation in serrated lesions. Notably, only serrated lesions exhibit a fetal gene expression program, suggesting a potential link to epigenetically deregulated TE expression mediated by the PIWI-piRNA pathway. We quantify and compare TE expression and methylation levels across subtypes of colorectal precancers and normal tissues, integrating these data with spatial transcriptomics to elucidate the relationship between TE expression and immune cell distribution. Our results reveal a significantly higher number of differentially expressed TEs in serrated lesions compared to conventional adenomas and suggest a positive association between TE expression and the immunogenic landscape in serrated lesions. These findings inform strategies to reprogram colorectal precancers toward an anti-tumor immune environment, offering potential benefits for cancer prevention and early immuno-intervention strategies in colorectal cancer. Citation Format: Zhengyi Chen, Sojung Lee, Alan J. Simmons, Robert J. Coffey, Martha J. Shrubsole, Jason W. Wong, Ken S. Lau. Understanding epigenetic-driven transposable re-expression and its impact on immune activation in the serrated pathway of colorectal tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2329.