Ontology highlight
ABSTRACT:
PROVIDER: PRJNA527992 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8752370_1.fastq.gz | Fastqsanger.gz | |||
| SRR8752370_2.fastq.gz | Fastqsanger.gz | |||
| SRR8752371_1.fastq.gz | Fastqsanger.gz | |||
| SRR8752371_2.fastq.gz | Fastqsanger.gz | |||
| SRR8752372_1.fastq.gz | Fastqsanger.gz |
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Project description:Acute myeloid leukemia (AML) has lagged in benefiting from immunotherapies, primarily due to the scarcity of actionable AML-specific antigens. While driver mutations are considered optimal sources for immunogenic targets, a comprehensive characterization of the AML driver mutational landscape and their resultant candidate neoantigens is lacking. Herein, we extensively integrated somatic mutation data from over 2,800 AML cases, identifying the driver genes in AML, notably characterized by a significant proportion of insertions and deletions (indels). Neoantigen prediction analysis revealed that indels triggered a higher abundance of neoantigens both in quantity and quality, compared with single nucleotide variants (SNVs) and gene fusions. We further integrated peptide features pertinent to neoantigen presentation and T cell recognition to establish two robust models of epitope immunogenicity that significantly enriched immunogenic neoepitopes derived from both gene mutations and fusions. The predicted number of neoantigens correlated with decreased survival in AML, partially attributed to the immunosuppressive microenvironment and exhausted CD8+ T cells, as supported by the deconvolution of large-scale bulk transcriptomes and the integration of single-cell RNA sequencing with multiparametric flow cytometry. Altogether, this study not only offers a valuable resource for adoptive cell-based therapy or personalized vaccine development but also underscores the necessity of incorporating strategies to revitalize the immunosuppressive milieu in conjunction with neoantigen-targeted therapies.
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Project description:Acute myeloid leukemia (AML) has lagged in benefiting from immunotherapies, primarily due to the scarcity of actionable AML-specific antigens. While driver mutations are considered optimal sources for immunogenic targets, a comprehensive characterization of the AML driver mutational landscape and their resultant candidate neoantigens is lacking. Herein, we extensively integrated somatic mutation data from over 2,800 AML cases, identifying the driver genes in AML, notably characterized by a significant proportion of insertions and deletions (indels). Neoantigen prediction analysis revealed that indels triggered a higher abundance of neoantigens both in quantity and quality, compared with single nucleotide variants (SNVs) and gene fusions. We further integrated peptide features pertinent to neoantigen presentation and T cell recognition to establish two robust models of epitope immunogenicity that significantly enriched immunogenic neoepitopes derived from both gene mutations and fusions. The predicted number of neoantigens correlated with decreased survival in AML, partially attributed to the immunosuppressive microenvironment and exhausted CD8+ T cells, as supported by the deconvolution of large-scale bulk transcriptomes and the integration of single-cell RNA sequencing with multiparametric flow cytometry. Altogether, this study not only offers a valuable resource for adoptive cell-based therapy or personalized vaccine development but also underscores the necessity of incorporating strategies to revitalize the immunosuppressive milieu in conjunction with neoantigen-targeted therapies.
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Project description:Whole Genome Sequencing of the murine breast cancer cell line 4T1 and of the murine melanoma cell line B16-ova was carried out with the aim of identifying somatic mutations. We also ran deep Mass Spectrometry proteomics analysis on the same cell lines, aiming to determine which somatic mutations carry over to the protein expression level. Further, we tested these cancer specific protein epitopes (putative neoantigens) for immunogenicity using mouse models. Finally, the putative neoantigens that showed good immunogenic potential were used in tumor growth control experiments with mice engrafted with the two tumor cell lines. In these experiments we tested whether cancer vaccines based on individual neoantigen peptides (MHC-I) restricted the growth of the tumor compared to adequate controls. The overall aim of the project is to validate the ability of our multi-omics/bioinformatics pipeline to identify and deliver neoantigens that can be used to suppress tumor growth. File names Sample names P10859_101_S1_L001_R1_001_BHKWV3CCXY 4T1_S1_L001_R1_001_BHKWV3CCXY P10859_101_S1_L001_R2_001_BHKWV3CCXY 4T1_S1_L001_R2_001_BHKWV3CCXY P10859_101_S1_L002_R1_001_BHKWV3CCXY 4T1_S1_L002_R1_001_BHKWV3CCXY P10859_101_S1_L002_R2_001_BHKWV3CCXY 4T1_S1_L002_R2_001_BHKWV3CCXY P10859_102_S2_L003_R1_001_BHKWV3CCXY B16-OVA_S2_L003_R1_001_BHKWV3CCXY P10859_102_S2_L003_R2_001_BHKWV3CCXY B16-OVA_S2_L003_R2_001_BHKWV3CCXY P10859_102_S2_L004_R1_001_BHKWV3CCXY B16-OVA_S2_L004_R1_001_BHKWV3CCXY P10859_102_S2_L004_R2_001_BHKWV3CCXY B16-OVA_S2_L004_R2_001_BHKWV3CCXY
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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.
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