Multi-omics discovery of exome-derived neoantigens in hepatocellular carcinoma

Genome Medicine

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[1] 0000 0001 0196 8249, grid.411544.1, Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, D-72076, Tübingen, Germany;0000 0001 0196 8249, grid.411544.1, Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, D-72076, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, D-72076, Tübingen, Germany;German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany;0000 0001 0196 8249, grid.411544.1, Department of Clinical Pharmacology, University Hospital Tübingen, Auf der Morgenstelle 8, D-72076, Tübingen, Germany;0000 0001 0196 8249, grid.411544.1, Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, D-72076, Tübingen, Germany;German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany;0000 0001 0196 8249, grid.411544.1, Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, D-72076, Tübingen, Germany;Present address: Department of General and Visceral Surgery, Schwarzwald-Baar Hospital, Klinikstr. 11, D-78052, Villingen-Schwenningen, Germany;0000 0001 0196 8249, grid.411544.1, Institute for Translational Bioinformatics, University Hospital Tübingen, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, Quantitative Biology Center (QBiC), University of Tübingen, Auf der Morgenstelle 10, D-72076, Tübingen, Germany;0000 0001 0196 8249, grid.411544.1, Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Calwerstr. 7, D-72076, Tübingen, Germany;0000 0001 0196 8249, grid.411544.1, Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Calwerstr. 7, D-72076, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, NGS Competence Center Tübingen (NCCT), University of Tübingen, Tübingen, Germany;0000 0001 0196 8249, grid.411544.1, Institute of Pathology and Neuropathology, University Hospital Tübingen, Liebermeisterstr. 8, D-72076, Tübingen, Germany;0000 0001 0807 2568, grid.417893.0, Cancer Immunoregulation Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale” – IRCCS, 80131, Naples, Italy;0000 0001 2190 1447, grid.10392.39, Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, D-72076, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, D-72076, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, Center for Bioinformatics, University of Tübingen, Sand 14, D-72076, Tübingen, Germany;Department of Computer Science, Applied Bioinformatics, Sand 14, D-72076, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, D-72076, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, Center for Bioinformatics, University of Tübingen, Sand 14, D-72076, Tübingen, Germany;Department of Computer Science, Applied Bioinformatics, Sand 14, D-72076, Tübingen, Germany;0000 0000 9709 7726, grid.225360.0, Present address: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, CB10 1SD,, Cambridgeshire, United Kingdom;0000 0001 2190 1447, grid.10392.39, Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, D-72076, Tübingen, Germany;0000 0004 0560 4823, grid.434836.e, Present address: Immatics Biotechnologies GmbH, Paul-Ehrlich-Str. 15, D-72076, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, D-72076, Tübingen, Germany;German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, D-72076, Tübingen, Germany;German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, Internal Medicine, Department for Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University of Tübingen, Otfried-Müller-Str. 10, D-72076, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, Interfaculty Institute for Cell Biology, Proteome Center Tübingen (PCT), University of Tübingen, Auf der Morgenstelle 15, 72076, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, Quantitative Biology Center (QBiC), University of Tübingen, Auf der Morgenstelle 10, D-72076, Tübingen, Germany;German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany;0000 0001 0196 8249, grid.411544.1, Institute for Translational Bioinformatics, University Hospital Tübingen, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, Quantitative Biology Center (QBiC), University of Tübingen, Auf der Morgenstelle 10, D-72076, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, Center for Bioinformatics, University of Tübingen, Sand 14, D-72076, Tübingen, Germany;Department of Computer Science, Applied Bioinformatics, Sand 14, D-72076, Tübingen, Germany;0000 0001 2190 1447, grid.10392.39, NGS Competence Center Tübingen (NCCT), University of Tübingen, Tübingen, Germany;0000 0001 1014 8330, grid.419495.4, Max Planck Institute for Developmental Biology, Biomolecular Interactions, Spemannstr. 35, D-72076, Tübingen, Germany;

关键词: Hepatocellular carcinoma;    HLA;    HLA ligandomics;    Immunoinformatics;    Immunotherapy;    Liver cancer;    Mass spectrometry;    Multi-omics;    Neoantigen;    Next-generation sequencing;    Peptide prediction;    Personalized medicine;   

DOI  :  10.1186/s13073-019-0636-8

来源: publisher

【 摘 要 】

BackgroundAlthough 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.MethodsIn-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.ResultsThe 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.ConclusionsThis 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.

【 授权许可】

CC BY