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DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts [Ribo-Seq]

ABSTRACT: DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts [Ribo-Seq]

PROVIDER: PRJNA862448 | ENA |

REPOSITORIES: ENA

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DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts

Project description:Immunotherapies targeting cancer-specific immunogenic neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies could synergize with immunotherapies, mediating the de-repression of endogenous retroviral element (ERV)-encoded promoters, and the initiation of transcription. Here we use RNA sequencing from cancer cells treated with DNMT and/or HDAC inhibitors, to assemble a de novo transcriptome and identified 3,023 ERV-derived, treatment-induced novel polA+ transcripts (TINPATs), encoding for 61,426 novel open reading frames. We further demonstrate, using human leukocyte antigen immunopeptidomics, the existence of treatment-induced neoepitopes (t-neoepitopes) derived from TINPATs. We demonstrated the potential of the identified t-neoepitopes to elicit an immunogenic T-cell response and cancer cell killing. The presence of t-neoepitopes was further verified in AML patient samples 48 h and /96 h after in vivo treatment with the DNMT inhibitor Decitabine. Our findings highlight a novel mechanism of ERV-derived neoantigens in epigenetic and immune therapies.

2023-09-13 | PXD035748 | Pride

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts

Project description:Immunotherapies targeting cancer-specific neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies synergize with immunotherapies, mediated bythe de-repression of endogenous retroviral element (ERV)-encoded promoters, and the initiation of transcription. Here, we use deep RNA sequencing from cancer cell lines treated with DNA methyltransferase inhibitors (DNMTi) and/or Histone deacetylase transferase inhibitors (HDACi), to assemble a de novo transcriptome and identified 3,023 ERV-derived, treatment-induced novel polyadenylated transcripts (TINPATs), encoding for 61,426 open reading frames. Using Immunopeptidomics, we further demonstrate the human leukocyte antigen (HLA) presentation of treatment-induced neoepitopes (t-neoepitopes) derived from TINPATs. We illustrate the potential of the identified t-neoepitopes to elicit a T-cell response and cancer cell killing. The presence of t-neoepitopes was further verified in AML patient samples 48/96 h after in vivo treatment with the DNMT inhibitor Decitabine. Our findings highlight a novel mechanism of ERV-derived neoantigens in epigenetic and immune therapies.

2023-08-18 | PXD035750 | Pride

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts

Project description:DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts

| PRJNA862442 | ENA

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts [RNA-Seq]

Project description:DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts [RNA-Seq]

| PRJNA862388 | ENA

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts [Ribo-Seq]

Project description:To investigate the effect of Decitabine and SB939 treatment on the expression of endoretroviral elements. We treated NCI-H1299 cells with DMSO or a combination of Decitabine and SB939 and performed Ribo-seq. This data was used to identify novel ORFs expressed from endoretroviral elements derived transcripts.

2023-08-22 | GSE209776 | GEO

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-08-22 | GSE209777 | GEO

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts [RNA-Seq]

Project description:To investigate the effect of Decitabine and SB939 treatment on the expression of endoretroviral elements. We treated 9 cell lines with DMSO, Decitabine, SB939 or a combination of Decitabine and SB939 and performed RNA-seq. This data was used to generate a denovo transcriptome assembly to identify novel mRNAs expressed from endoretroviral elements.

2023-08-22 | GSE209772 | GEO

Reactivation of endogenous retroviral elements via treatment with DNMT- and HDAC-inhibitors.

Project description:Inhibitors of DNA methyltransferases (DNMTis) or histone deacetylases (HDACis) are epigenetic drugs which are investigated since decades. Several have been approved and are applied in the treatment of hematopoietic and lymphatic malignancies, although their mode of action has not been fully understood. Two recent findings improved mechanistic insights: i) activation of human endogenous retroviral elements (HERVs) with concomitant synthesis of double-stranded RNAs (dsRNAs), and ii) massive activation of promoters from long terminal repeats (LTRs) which originated from past HERV invasions. These dsRNAs activate an antiviral response pathway followed by apoptosis. LTR promoter activation leads to synthesis of non-annotated transcripts potentially encoding novel or cryptic proteins. Here, we discuss the current knowledge of the molecular effects exerted by epigenetic drugs with a focus on DNMTis and HDACis. We highlight the role in LTR activation and provide novel data from both in vitro and in vivo epigenetic drug treatment.

| S-EPMC6056222 | biostudies-literature

Systematic identification of recurrent immunogenic neoantigens in treatment-resistant tumors

Project description:Recurrent neoantigens in treatment-resistant tumors

| PRJEB79570 | ENA

Expression profiling of mouse melanomas with or without UVB-induced neoantigens and after combination immunotherapy

Project description:Syngeneic grafts of the D4M.3A.3 (parental) mouse melanoma cell line (derived from a Tyr::CreER;BrafCA;Ptenlox/lox mouse) in C56BL/6 mice model poorly immunogenic, low neoantigen human melanomas. The D3UV2 (UV2) cell line was derived by serial UVB irradiation and single cell cloning. The addition of UVB-induced putative neoantigens sensitizes UV2 syngeneic melanoma grafts to immune checkpoint inhibitors and triggers epitope skewing to tumor-lineage self-antigens, a phenomenon that can be successfully mimicked in parental melanomas through treatment combinations such as anti-PD-1 with ablative fractional photothermolysis and imiquimod. Our mouse models were used to characterize gene expression changes between neoantigen rich and neoantigen poor melanomas, and with immunotherapy.

2021-02-16 | GSE159344 | GEO

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