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Pan-cancer tumor-specific antigens and membrane targets from transposable elements

ABSTRACT: We charted the transcription start sites (TSSs) landscape globally to determine the expressed isoform of each gene and validate the precence of transposable element-derived transcript. Cryptic promoters within transposable elements (TEs) are transcriptionally reactivated in tumors to create novel TE-gene chimeric transcripts, which can produce immunogenic antigens. We performed the most comprehensive screen to date for these TE exaptation events in 33 TCGA tumortypes,675 cancer cell lines, and 11,686 GTEx adult tissue transcriptomes and identified 201,068 TE-exapted candidates with the potential to generate shared tumor-specific TE-chimeric antigens (TS-TEAs). Resultant whole lysate and HLA-pull down mass spectrometry data confirmed that TS-TEAs are presented on cancer cell surfaces. In addition, we highlight the tumor-specific membrane proteins transcribed from TE promoters that can expose novel epitopes on the extracellular surface of cancer cells. Here, we showcase the high pan-cancer prevalence of TS-TEAs and atypical membrane proteins that can be therapeutically exploited through immunotherapy approaches.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201021 | GEO | 2023/01/20

REPOSITORIES: GEO

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Pan-cancer tumor-specific antigens and membrane targets from transposable elements

Project description:Cryptic promoters within transposable elements (TEs) are transcriptionally reactivated in tumors to create novel TE-gene chimeric transcripts, which can produce immunogenic antigens. We performed the most comprehensive screen to date for these TE exaptation events in 33 TCGA tumor types, 675 cancer cell lines, and 11,686 GTEx adult tissue transcriptomes and identified 1,068 TE-exapted candidates with the potential to generate shared tumor-specific TE-chimeric antigens (TS-TEAs). Resultant whole lysate and HLA-pulldown mass spectrometry data confirmed that TS-TEAs are presented on cancer cell surfaces. In addition, we highlight the tumor-specific membrane proteins transcribed from TE promoters that can expose novel epitopes on the extracellular surface of cancer cells. Here, we showcase the high pan-cancer prevalence of TS-TEAs and atypical membrane proteins that can be therapeutically exploited through immunotherapy approaches.

2023-01-21 | PXD033351 | Pride

Using long-read CAGE sequencing to profile cryptic-promoter derived transcripts and their contribution to the immunopeptidome

Project description:Recent studies have demonstrated that the non-coding genome can produce unannotated proteins as antigens that induce immune response. One major source of this activity is the aberrant epigenetic reactivation of transposable elements (TEs). In tumors, TEs often provide cryptic or alternate promoters, which can generate transcripts that encode tumor-specific unannotated proteins. Thus, TE-derived transcripts have the potential to produce tumor-specific, but recurrent, antigens shared among many tumors. Identification of TE-derived tumor antigens holds the promise to improve cancer immunotherapy approaches; however, current genomics and computational tools are not optimized for their detection. Here we combined CAGE technology with full-length long-read transcriptome sequencing (Long-Read CAGE, or LRCAGE) and developed a suite of computational tools to significantly improve immunopeptidome detection by incorporating TE-derived and other tumor transcripts into the proteome database. By applying our methods to human lung cancer cell line H1299 data, we demonstrated that long-read technology significantly improves mapping of promoters with low mappability scores and LRCAGE guarantees accurate construction of uncharacterized 5’ transcript structure. Unannotated peptides predicted from newly characterized transcripts were readily detectable in whole cell lysate mass-spectrometry data. Incorporating unannotated peptides into the proteome database enabled us to detect non-canonical antigens in HLA-pulldown LC-MS/MS data. At last, we showed that epigenetic treatment increased the number of non-canonical antigens, particularly those encoded by TE-derived transcripts, which might expand the pool of targetable antigens for cancers with low mutational burden.

2023-09-23 | PXD040265 | Pride

Non-canonical splicing junctions between exons and transposable elements represent a source of immunogenic recurrent neo-antigens in cancer patients

Project description:ost characterized tumor antigens are ‘genomic’, i.e. encoded by canonical, non-canonical or somatically mutated genomic sequences. We investigate here the presentation and immunogenicity of tumor antigens derived from non-canonical mRNA splicing events between coding exons and transposable elements (TEs). Comparing non-small cell lung cancer (NSCLC), an immunogenic tumor type, and diverse non-tumor tissues, we identify several thousand splicing junctions between exons and diverse TE classes. A subset of these junctions is both tumor-specific and shared across patients. HLA-I peptidomic identifies peptides encoded by tumor-specific junctions in primary NSCLC samples and lung tumor cell lines. Recurrent junction-encoded peptides are immunogenic in vitro and CD8+ T cells specific for junction-encoded epitopes are present in tumors and tumor-draining lymph nodes from NSCLC patients. We conclude that non-canonical splicing junctions between exons and TEs represent a source of recurrent, immunogenic tumor-specific antigens in NSCLC cancer patients.

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Widespread transposable element-driven oncogene expression in cancers

Project description:Transposable elements act as promiscuous cryptic promoters that upregulate oncogenes (“onco-exaptation”) in many cancers.

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High-throughput screen for genes predominantly expressed in the ICM of mouse blastocysts by whole mount in situ hybridiz

Project description:We attempted to identify candidate genes that are expressed more highly in the ICM than in TE cells. Mouse ES cells are cultured from the ICM, whereas mouse TS cells are cultured from the TE. Although these cells have been cultured in vitro, they represent the in vitro equivalents of the ICM and TE. Therefore, genes which are expressed more highly in ES than TS in microarray studies were good candidates for genes predominantly expressed in the ICM in blastocysts. We attempted to identify candidate genes that are expressed more highly in the ICM than in TE cells. Mouse ES cells are cultured from the ICM, whereas mouse TS cells are cultured from the TE. Although these cells have been cultured in vitro, they represent the in vitro equivalents of the ICM and TE. Therefore, genes which are expressed more highly in ES than TS in microarray studies were good candidates for genes predominantly expressed in the ICM in blastocysts.

2010-06-09 | E-GEOD-3214 | biostudies-arrayexpress

TE-Array-- A high throughput tool to study transposon transcription

Project description:TE-Array is a custom Agilent microarray that probes for transposable elements in both sense and antisense orientations in humans and mice. TE-Array was used to study expression levels of transposable elements (TE) in a panel of normal mouse tissues. TE-Array comprises of 4 different custom Agilent 4X44K designs. These 4 different designs have probes for human sense orientation, human antisense orientation, mouse sense orientation and mouse antisense orientation transposable elements. These array designs were used to study the transposon abundance profile in 7 different mouse tissue samples, 2 mouse cell lines and 1 transposon transfected versus untransfected human cell line.

2013-11-16 | E-GEOD-52412 | biostudies-arrayexpress

LC-MSMS of the MHC-I immunopeptidome of murine thymic epithelial cells

Project description:Antigen presentation by cortical and medullary thymic epithelial cells (cTEC and mTEC) ensures the formation of a self-restricted and self-tolerant T cell repertoire, respectively. As such, a broad diversity of self-antigens needs to be presented by mTEC to induce T cell’s self-tolerance. Even though the expression and antigen presentation of protein coding genes in mTEC has been abundantly described, little is known of the implication of allegedly noncoding regions of the genome to tolerance induction. In this study, we focused on transposable elements (TE), which have been shown to be highly expressed by mTEC.

2024-04-17 | PXD042241 | Pride

Transcription profiling of mouse embryonic stem vs trophoblastic stem cells

2005-01-01 | E-MNIA-73 | biostudies-arrayexpress

TE-Array-- A high throughput tool to study transposon transcription

2013-11-16 | GSE52412 | GEO

Transposon-activated POU5F1B promotes colorectal cancer growth and metastasis I

Project description:Tumors occasionally express oncogenes via aberrant activation of transposable elements (TE), but a role for this process in oncogenesis was seldom demonstrated. Here, we identify expression of the hominid-restricted retrogene POU5F1B through aberrant activation of an endogenous retroviral promoter as a strong negative prognostic marker in colorectal cancer (CRC). We further determine that POU5F1B is membrane-enriched and interacts with ERBB2 and associated effectors, and fosters the proliferation and metastatic potential of CRC cells through intracellular signaling events and release of trans-acting molecules involved in cell growth, angiogenesis and cell adhesion. As POU5F1B is apparently non-essential and only lowly expressed in normal tissues, and as POU5F1B-containing TE-driven transcripts are detected in other tumors besides CRC, these data provide interesting leads for the development of cancer therapies.

2022-08-02 | GSE161083 | GEO

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