Transposable Element Exprssion in Tumors is Associated with Immune Infiltration and Increased Antigenicity

Abstract

Profound loss of DNA methylation is a well-recognized hallmark of cancer. Given its role in silencing transposable elements (TEs), we hypothesized that extensive TE expression occurs in tumors with highly demethylated DNA. We developed REdiscoverTE, a computational method for quantifying genome-wide TE expression in RNA sequencing data. Using The Cancer Genome Atlas database, we observed increased expression of over 400 TE subfamilies, of which 262 appeared to result from a proximal loss of DNA methylation. The most recurrent TEs were among the evolutionarily youngest in the genome, predominantly expressed from intergenic loci, and associated with antiviral or DNA damage responses. Treatment of glioblastoma cells with a demethylation agent resulted in both increased TE expression and de novo presentation of TE-derived peptides on MHC class I molecules. Therapeutic reactivation of tumor-specific TEs may synergize with immunotherapy by inducing both inflammation and the display of potentially immunogenic neoantigens.One Sentence Summary: Transposable element expression in tumors is associated with increased immune response and provides tumor-associated antigens All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Three-dimensional and single-cell sequencing of liver cancer reveals comprehensive host-virus interactions in HBV infection

“…Third, we identified HBV-associated large SVs resulting in 3D genome changes that affect tumor suppressors including PROS1 and NLGN4Y. Finally, we combined public scRNA-seq with our HiC data to further investigate HBVassociated TE reactivation in liver cancer patients, which may indicate better immunotherapeutic responses (41). Collectively, we believe that our study has the potential to better inform future clinical practice related to HBV infection in liver cancer patients.…”

Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation

“…However, our study reveals that this phenomenon extends beyond tumors, as irradiated non-tumor cells also express these immune-enhancing elements. This emphasize the pivotal role of TEs in enhancing IFN1 response not only in tumors and age-associated disorders 29,[50][51][52] but also in irradiated normal tissue-derived stem/progenitor cells. Importantly, TEs are tightly regulated, and their expression can be profoundly affected by alterations in chromatin accessibility 28,31 .…”

Comprehensive locus-specific L1 DNA methylation profiling reveals the epigenetic and transcriptional interplay between L1s and their integration sites

“…Knocking out any component of the HUSH complex indeed leads to a massive increase of L1 expression in these cells where L1PA elements appear to be virtually devoid of DNA methylation (Figure 2), but has more modest effects in other cell types 43 . Reactivation of retrotransposons, including L1 elements, by epigenetic drugs is a promising approach for cancer treatment as RNA species produced can establish a state of "viral mimicry", which stimulates antitumor immunity 45,[112][113][114][115][116] . By showing that only a fraction of L1HS loci can be reactivated by a DNA demethylating drug, our results underscore the need to precisely delineate the specific pathways responsible for the silencing of individual loci, in order to rationally elaborate drug combinations capable of specifically and massively re-expressing L1 elements.…”