Pan-cancer analysis identifies tumor-specific antigens derived from transposable elements

Shah, Nakul; Jang, Haeyeon; Liang, Yonghao; Maeng, Ju Heon; Tzeng, Shin‐Cheng; Wu, Angela Ruohao; Basri, Noah L.; Qu, Xuan; Fan, Changxu; Li, Amy; Katz, Benjamin; Li, Daofeng; Evans, Bradley S.; Wang, Ting

doi:10.1038/s41588-023-01349-3

Cited by 69 publications

(36 citation statements)

References 66 publications

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“…Boxplots showing the expression of TE-chimeric transcripts in A375, GP5d, OE19 and GP5d p53-KO cells with and without SETDB1 inhibition/KO. Expression of TE-chimeric transcripts were determined by TEprof2 analysis pipeline 23 . P values were calculated with a two-sided, Wilcoxon test (n = 53, 24, 144 and 141 differentially expressed TE-chimeric transcripts in A375, GP5d, OE19 and GP5d p53-KO cells, respectively).…”

Section: Resultsmentioning

confidence: 99%

“…Earlier studies have shown that TEs epigenetically deregulated in cancer can serve as cryptic promoters and splice into nearby protein coding genes to form TE-chimeric transcripts 21–23 . These transcripts can produce TE-chimeric peptides that can serve as cancer-specific antigens and thus exploited to target cancer cells 22,23 . To study the effect of SETDB1 inhibition on TE-chimeric expression, we performed TEProf2 23 analysis on RNA-seq data in A375, GP5d, OE19 and GP5d p53-KO cells.…”

Section: Resultsmentioning

confidence: 99%

“…Epigenetic therapy such as inhibition of DNA methyltransferases (DNMTi) or co-inhibition of DNMT and histone deacetylases (DNMTi-HDACi) activates cryptic promoter within TEs that can splice into nearby protein coding genes to transcribe TE-chimeric transcripts 21,22 . TE-chimeric transcripts encode immunogenic antigen in cancer cells that can be targeted for immune therapy 21–23 . Human endogenous retrovirus (HERV) elements from the LTR12C subfamily derepressed by DNMTi or DNMTi-HDACi mainly contributes to immunogenic TE-chimeric transcripts 21,22 .…”

Section: Introductionmentioning

confidence: 99%

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Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes

Patel,

Tiusanen,

Pihlajamaa

et al. 2024

Preprint

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The combination of immunotherapy and epigenetic therapy is emerging as a promising approach for cancer therapy. Epigenetic therapy can induce derepression of transposable elements (TEs) that play a major role in activation of immune response against cancer cells. However, the molecular mechanism of TE regulation by distinct chromatin modifier enzymes (CME) and in the context of p53 is still elusive. Here, we used epigenetic drugs to inhibit distinct CMEs in p53 wild-type and p53-mutant colorectal and esophageal cancer cells. We show that distinct TEs subfamilies are derepressed by inhibition of different CMEs in a cell-type specific manner with loss of p53 resulting in stronger TE derepression. We show that KAP1, a known repressor of TEs, associates with stronger derepression of specific TE subfamilies such as LTR12C, indicating that KAP1 also has an activating role in TE regulation in cancer cells upon co-inhibition of DNMT and HDAC. Co-inhibition of DNMT and HDAC activates immune response by inducing inverted repeat Alu expression, reducing ADAR1-mediated Alu RNA editing, and inducing cell type-specific TE-chimeric transcript expression. Collectively, our study demonstrates that inhibition of different CMEs results in derepression of distinct TEs in cell type-specific manner and by utilizing distinct mechanistic pathways, providing insights for epigenetic therapies that could selectively enhance anti-tumor immunity in distinct cancer types.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes

Patel,

Tiusanen,

Pihlajamaa

et al. 2024

Preprint

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“…Importantly, depletion of H3K9me3 in GBM cells resulted in the upregulation of repetitive sequence expression, downregulation of the cell cycle, and induction of the immune responses. Intriguingly, a prior study uncovered the presence of tumor-specific antigens originating from certain repetitive sequences in various cancers, potentially eliciting immune responses (47). These findings offer compelling experimental evidence supporting our hypothesis that the H3K9me3 MtSig regulates cancer cell cycle and immune responses through H3K9me3-mediated silencing of repetitive sequences.…”

Section: Discussionmentioning

confidence: 99%

Multi-omic Analysis Identifies Glioblastoma Dependency on H3K9me3 Methyltransferase Activity

Xie,

Du,

Ghosh

et al. 2024

Preprint

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Histone H3 Lysine 9 dimethylation or trimethylation (H3K9me2 or H3K9me3) marks more than half of the human genome, particularly in heterochromatin regions and specific genes within euchromatic regions. Enzymes catalyzing the methylation of H3K9 have individually been associated with the modulation of gene expression patterns involved in cancer progression, including suppressor of variegation 3-9 homologue 1 (SUV39H1), SUV39H2, SET domain bifurcated 1 (SETDB1), SETDB2, euchromatic histone-lysine N-methyltransferase 1 and 2 (EHMT1/2). However, a comprehensive comparison and understanding of the characteristics and mechanisms of these chromatin-modifying enzymes in cancers remains incompletely understood. In this study, we demonstrated that these six H3K9 methyltransferases differentially expressed in tumors and correlated expression with somatic copy number variations (CNVs) and DNA methylation patterns. Through integrative multi-omics analyses, we identified SUV39H1, SUV39H2, and SETDB1 as the key players among the six H3K9 methyltransferases that exhibited the most significant associations with cancer phenotypes. By incorporating SUV39H1, SUV39H2, and SETDB1, we developed a novel signature termed "H3K9me3 MtSig" (H3K9me3 methyltransferases signature). H3K9me3 MtSig was unique for various tumor types, had prognostic implications and was linked to significant signaling pathways, particularly in glioblastoma (GBM). Furthermore, elevated H3K9me3 MtSig was confirmed in GBM patient-derived cells and tissues. In addition, single-cell expression analysis of H3K9me3 MtSig in GBM tissues demonstrated a pattern related to the G2/M cell cycle and was negatively correlated with immune responses. H3K9me3-mediated repetitive sequence silencing by H3K9me3 MtSig, determined using ChIP-sequencing, contributed to these phenotypes, and inhibiting H3K9me3 MtSig in patient-derived GBM cells suppressed proliferation and increased immune responses. Translationally, H3K9me3 MtSig performed as an independent prognostic factor in a clinical prediction model, and drug susceptibility screening integrating H3K9me3 MtSig identified potential biomarkers and therapeutics for GBM. In summary, H3K9me3 MtSig has the potential to elucidate novel prognostic markers, therapeutic targets, and predictors of treatment response in GBM and other cancer types for clinical intervention.

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“…Their profiling will require MS analyses of enormous numbers of TECs or the development of more sensitive MS techniques. As TE MAPs have been detected in normal and neoplastic extrathymic cells (34,(85)(86)(87), the presentation of TEs by mTECs is likely essential to central tolerance. In line with vibrant plaidoyers for a collaborative Human Immunopeptidome Project (66,88), our work suggests that immunopeptidomic studies should not be limited to protein-coding genes (2% of the genome) but also encompass non-coding sequences such as TEs.…”

Section: Discussionmentioning

confidence: 99%

Transposable elements regulate thymus development and function

Laumont

Trofimov

Vincent

et al. 2023

Preprint

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Transposable elements (TE) are repetitive sequences representing ∼45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTEC). In this study, we investigated the role of transposable elements (TE), which are highly expressed by medullary thymic epithelial cells (mTEC), on T-cell development in the thymus. We performed multi-omic analyses of TEs in human and mouse thymic cells to elucidate their role in T cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TEs interact with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDC). In mTECs, TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and RELB) and generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that lead to the formation of dsRNA, triggering RIG-I and MDA5 signaling and explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study illustrates the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that the orchestration of TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.

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Pan-cancer analysis identifies tumor-specific antigens derived from transposable elements

Cited by 69 publications

References 66 publications

Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes

Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes

Multi-omic Analysis Identifies Glioblastoma Dependency on H3K9me3 Methyltransferase Activity

Transposable elements regulate thymus development and function

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