Abstract B007: Epigenetic reactivation of transposable elements as prognostic markers for PD1/PDL1 immunotherapy in cancer

Abstract Transposable elements (TEs), once considered as "junk" DNA, are now recognized for their epigenetic and regulatory influence, especially in cancer. Cryptic regulatory elements within TEs can be epigenetically reactivated in cancer, contributing to oncogenesis and altering gene expression patterns. This reactivation results in TE-derived transcripts, which have the potential to be translated and form neoantigens that can be presented by the human leukocyte antigens (HLA) complex and recognized by T cells, ultimately impacting the tumor immune response. In this study, we analyzed RNA-seq data from melanoma patients undergoing PD1/PDL1 immunotherapy. By identifying tumor specific TE-derived transcripts and utilizing in silico translation, we detected TE-derived neoantigens in patients with differing responses to immunotherapy. Our findings indicate that the number of TE-derived neoantigens is correlated with patients' response to immunotherapy, with a higher number of neoantigens observed in patients who responded to treatment compared to those who did not. These results imply that TE-derived neoantigens may serve as potential biomarkers for predicting the prognosis of PD1/PDL1 immunotherapy treatment. Incorporating TE-derived neoantigen profiles into clinical decision-making could enhance patient selection for immunotherapy, thereby improving treatment outcomes. Citation Format: Yixin Wu, Ting Wang, Yonghao Liang. Epigenetic reactivation of transposable elements as prognostic markers for PD1/PDL1 immunotherapy in cancer [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 B007.