Abstract B024: Transposable elements activation produces pan-cancer tumor-specific neoantigens

Abstract Immunotherapy has been a promising treatment for various cancer types. This therapy heavily relies on the efficiency of the targeted neoantigens for T cell recognition and downstream immune responses. Neoantigens derived from tumor-specific nonsynonymous somatic mutations have been a great resource and manifested remarkable therapeutic effects, yet with high patient specificity and high dependency on mutation rate. Here, we propose a novel strategy for discovering neoantigens derived from epigenetic mutations, rather than genetic mutations, from transposable elements (TEs) sequences. TEs make up 50% of the human genome but have been long considered to be “junk DNA” and therefore overlooked in medical genomics. However, recent works from our lab have shown that, despite being epigenetically silenced in somatic cells, certain TEs contribute significantly to the evolution of regulatory networks and shape the cancer transcriptome landscape, including functioning as promoters and producing novel, tumor-specific TE-derived transcripts (TSTETs) that can be translated into proteins. Given the plasticity of epigenome, neoantigens resulted from epigenetic mutations could be pan-cancer with high recurrence. Thus, we hypothesize that cryptic promoters embedded in TEs can be re-activated due to epigenetic dysregulation in cancer, leading to the generation of highly recurrent, pan-cancer, TE-derived, tumor-specific protein products that could be employed as neoantigens for immuno-therapy. In this study, we developed a computational pipeline termed TE Promoter Finder 3 (TEProf3) to precisely identify TE-derived promoters and transcripts genome-wide from transcriptomic data, including data from both long-read and short-read sequencing. We applied TEProf3 to analyze 12,015 tumor samples encompassing 33 cancer types from The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets. Our analysis revealed 14,417 of TSTETs and hundreds of tumor-specific TE-derived antigens (TSTEAs) from the tumor transcriptomic and mass spectrometry data, respectively. Notably, most TSTETs exhibited high recurrence rates, with over 10% recurrence in the majority and some exceeding 90% recurrence. Each tumor sample displayed a median number of 19 TSTETs. Certain cancer types showed a comparable landscape of tumor-specific TE-derived promoters, potentially due to similarities in epigenetic mutations and cell types of origin. The number of TSTETs correlated with tumor progression in some cancer types, suggesting a link between progressive dysregulation of TE-derived promoters and tumorigenesis. We further assessed the efficiency of antigen presentation in cancer cell lines as a proof of concept. We successfully identified T cell receptors sequences from CD8+ T cells that exhibited strong binding affinity for TSTEAs and demonstrated cytotoxicity effects on the cancer cell lines. In summary, this work represents one of the first comprehensive catalogs of TSTEAs, providing a valuable resource for future immunotherapy strategies. Citation Format: Yonghao Liang, Xiaoyun Xing, Ting Wang. Transposable elements activation produces pan-cancer tumor-specific neoantigens [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B024.