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Title:
Multi-omics discovery of exome-derived neoantigens in hepatocellular carcinoma | Genome Medicine
Description:
Background Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics approach comprising a neoepitope identification pipeline, we assessed exome-derived mutations naturally presented as HLA class I ligands in HCCs. Methods In-depth multi-omics analyses included whole exome and transcriptome sequencing to define individual patient-specific search spaces of neoepitope candidates. Evidence for the natural presentation of mutated HLA ligands was investigated through an in silico pipeline integrating proteome and HLA ligandome profiling data. Results The approach was successfully validated in a state-of-the-art dataset from malignant melanoma, and despite multi-omics evidence for somatic mutations, mutated naturally presented HLA ligands remained elusive in HCCs. An analysis of extensive cancer datasets confirmed fundamental differences of tumor mutational burden in HCC and malignant melanoma, challenging the notion that exome-derived mutations contribute relevantly to the expectable neoepitope pool in malignancies with only few mutations. Conclusions This study suggests that exome-derived mutated HLA ligands appear to be rarely presented in HCCs, inter alia resulting from a low mutational burden as compared to other malignancies such as malignant melanoma. Our results therefore demand widening the target scope for personalized immunotherapy beyond this limited range of mutated neoepitopes, particularly for malignancies with similar or lower mutational burden.
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Keywords {🔍}
pubmed, hla, google, scholar, hcc, cas, cancer, mel, central, data, pne, additional, tübingen, mutated, ligands, tumor, table, analysis, evidence, patients, peptides, file, peptide, database, varns, class, nelig, mutations, variants, level, dataset, liver, germany, somatic, hccs, proteome, neoepitopes, numbers, mass, nonmalignant, protein, ligandome, predicted, samples, fig, hepatocellular, previously, gene, average, university,
Topics {✒️}
org/content/disease/lung-cancer/pik3ca/7/ hans-georg rammensee analysis-ready rna-seq datasets t-cell-dependent mechanism bulk multi-omics analysis mass spectrometry-based proteomics vaccine induced afp-specific hhla2 activates c-met anti-epidermal growth factor multi-allelic hla class boxplots show means ± sd semi-random sampling inherent tumor-derived raw files targetable tumor-specific antigens open-source software library data-driven biomedical research full size image coomassie-stained gel pieces tailored neoantigen-targeted immunotherapies uhplc-coupled ms/ms tumor-specific mutations presented afp-positive hepatocellular cancer wild-type peptide sequence wild-type sequence peptide wild-type hla ligands protein n-terminal acetylation heavy isotope-labeled peptides reproducible rna-seq analysis easylc nano-hplc system combining mass spectrometry pathway-based data integration proteome-wide protein quantification lc-ms/ms instrumentation personal tumor-specific neoantigens showed hla-binding properties quantitative biology center lc-ms/ms analysis multi-omics discovery long-term survival data identifier lc-ms/ms lc-ms data analysis biochemical large-scale identification peptide search space van buuren mm t-cell epitopes mutation-derived hla ligands hla ligandomics yields hla ligandomics data precision cancer medicine immunotherapy search search
Questions {❓}
- Predicting antigen presentation-what could we learn from a million peptides?
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headline:Multi-omics discovery of exome-derived neoantigens in hepatocellular carcinoma
description:Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics approach comprising a neoepitope identification pipeline, we assessed exome-derived mutations naturally presented as HLA class I ligands in HCCs. In-depth multi-omics analyses included whole exome and transcriptome sequencing to define individual patient-specific search spaces of neoepitope candidates. Evidence for the natural presentation of mutated HLA ligands was investigated through an in silico pipeline integrating proteome and HLA ligandome profiling data. The approach was successfully validated in a state-of-the-art dataset from malignant melanoma, and despite multi-omics evidence for somatic mutations, mutated naturally presented HLA ligands remained elusive in HCCs. An analysis of extensive cancer datasets confirmed fundamental differences of tumor mutational burden in HCC and malignant melanoma, challenging the notion that exome-derived mutations contribute relevantly to the expectable neoepitope pool in malignancies with only few mutations. This study suggests that exome-derived mutated HLA ligands appear to be rarely presented in HCCs, inter alia resulting from a low mutational burden as compared to other malignancies such as malignant melanoma. Our results therefore demand widening the target scope for personalized immunotherapy beyond this limited range of mutated neoepitopes, particularly for malignancies with similar or lower mutational burden.
datePublished:2019-04-30T00:00:00Z
dateModified:2019-04-30T00:00:00Z
pageStart:1
pageEnd:16
license:http://creativecommons.org/publicdomain/zero/1.0/
sameAs:https://doi.org/10.1186/s13073-019-0636-8
keywords:
Hepatocellular carcinoma
HLA
HLA ligandomics
Immunoinformatics
Immunotherapy
Liver cancer
Mass spectrometry
Multi-omics
Neoantigen
Next-generation sequencing
Peptide prediction
Personalized medicine
Human Genetics
Metabolomics
Bioinformatics
Medicine/Public Health
general
Cancer Research
Systems Biology
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ScholarlyArticle:
headline:Multi-omics discovery of exome-derived neoantigens in hepatocellular carcinoma
description:Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics approach comprising a neoepitope identification pipeline, we assessed exome-derived mutations naturally presented as HLA class I ligands in HCCs. In-depth multi-omics analyses included whole exome and transcriptome sequencing to define individual patient-specific search spaces of neoepitope candidates. Evidence for the natural presentation of mutated HLA ligands was investigated through an in silico pipeline integrating proteome and HLA ligandome profiling data. The approach was successfully validated in a state-of-the-art dataset from malignant melanoma, and despite multi-omics evidence for somatic mutations, mutated naturally presented HLA ligands remained elusive in HCCs. An analysis of extensive cancer datasets confirmed fundamental differences of tumor mutational burden in HCC and malignant melanoma, challenging the notion that exome-derived mutations contribute relevantly to the expectable neoepitope pool in malignancies with only few mutations. This study suggests that exome-derived mutated HLA ligands appear to be rarely presented in HCCs, inter alia resulting from a low mutational burden as compared to other malignancies such as malignant melanoma. Our results therefore demand widening the target scope for personalized immunotherapy beyond this limited range of mutated neoepitopes, particularly for malignancies with similar or lower mutational burden.
datePublished:2019-04-30T00:00:00Z
dateModified:2019-04-30T00:00:00Z
pageStart:1
pageEnd:16
license:http://creativecommons.org/publicdomain/zero/1.0/
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keywords:
Hepatocellular carcinoma
HLA
HLA ligandomics
Immunoinformatics
Immunotherapy
Liver cancer
Mass spectrometry
Multi-omics
Neoantigen
Next-generation sequencing
Peptide prediction
Personalized medicine
Human Genetics
Metabolomics
Bioinformatics
Medicine/Public Health
general
Cancer Research
Systems Biology
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name:University of Tübingen
address:
name:Interfaculty Institute for Cell Biology, Proteome Center Tübingen (PCT), University of Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:Boris Maček
affiliation:
name:University of Tübingen
address:
name:Interfaculty Institute for Cell Biology, Proteome Center Tübingen (PCT), University of Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:Sebastian P. Haen
affiliation:
name:University of Tübingen
address:
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen
address:
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:University of Tübingen
address:
name:Internal Medicine, Department for Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University of Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:Luigi Buonaguro
affiliation:
name:Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale” – IRCCS
address:
name:Cancer Immunoregulation Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale” – IRCCS, Naples, Italy
type:PostalAddress
type:Organization
name:Oliver Kohlbacher
affiliation:
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen
address:
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:University Hospital Tübingen
address:
name:Institute for Translational Bioinformatics, University Hospital Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:University of Tübingen
address:
name:Quantitative Biology Center (QBiC), University of Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:University of Tübingen
address:
name:Center for Bioinformatics, University of Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:Applied Bioinformatics
address:
name:Department of Computer Science, Applied Bioinformatics, Tübingen, Germany
type:PostalAddress
type:Organization
name:University of Tübingen
address:
name:NGS Competence Center Tübingen (NCCT), University of Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:Max Planck Institute for Developmental Biology, Biomolecular Interactions
address:
name:Max Planck Institute for Developmental Biology, Biomolecular Interactions, Tübingen, Germany
type:PostalAddress
type:Organization
name:Stefan Stevanović
affiliation:
name:University of Tübingen
address:
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen
address:
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:Alfred Königsrainer
affiliation:
name:University Hospital Tübingen
address:
name:Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen
address:
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:Hans-Georg Rammensee
affiliation:
name:University of Tübingen
address:
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen
address:
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany
type:PostalAddress
type:Organization
PostalAddress:
name:Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany
name:Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany
name:Institute for Translational Bioinformatics, University Hospital Tübingen, Tübingen, Germany
name:Quantitative Biology Center (QBiC), University of Tübingen, Tübingen, Germany
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
name:Center for Bioinformatics, University of Tübingen, Tübingen, Germany
name:Department of Computer Science, Applied Bioinformatics, Tübingen, Germany
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
name:Center for Bioinformatics, University of Tübingen, Tübingen, Germany
name:Department of Computer Science, Applied Bioinformatics, Tübingen, Germany
name:Present address: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridgeshire, United Kingdom
name:Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
name:Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
name:Present address: Immatics Biotechnologies GmbH, Tübingen, Germany
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
name:Present address: Immatics Biotechnologies GmbH, Tübingen, Germany
name:Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany
name:Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany
name:Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany
name:NGS Competence Center Tübingen (NCCT), University of Tübingen, Tübingen, Germany
name:Quantitative Biology Center (QBiC), University of Tübingen, Tübingen, Germany
name:Quantitative Biology Center (QBiC), University of Tübingen, Tübingen, Germany
name:Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
name:Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
name:Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
name:Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
name:Present address: Department of General and Visceral Surgery, Schwarzwald-Baar Hospital, Villingen-Schwenningen, Germany
name:Institute of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany
name:Institute of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany
name:Interfaculty Institute for Cell Biology, Proteome Center Tübingen (PCT), University of Tübingen, Tübingen, Germany
name:Interfaculty Institute for Cell Biology, Proteome Center Tübingen (PCT), University of Tübingen, Tübingen, Germany
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany
name:Internal Medicine, Department for Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University of Tübingen, Tübingen, Germany
name:Cancer Immunoregulation Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale” – IRCCS, Naples, Italy
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany
name:Institute for Translational Bioinformatics, University Hospital Tübingen, Tübingen, Germany
name:Quantitative Biology Center (QBiC), University of Tübingen, Tübingen, Germany
name:Center for Bioinformatics, University of Tübingen, Tübingen, Germany
name:Department of Computer Science, Applied Bioinformatics, Tübingen, Germany
name:NGS Competence Center Tübingen (NCCT), University of Tübingen, Tübingen, Germany
name:Max Planck Institute for Developmental Biology, Biomolecular Interactions, Tübingen, Germany
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany
name:Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany
name:Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
name:German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany
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