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

Markus W. Löffler, Christopher Mohr, Leon Bichmann, Lena Katharina Freudenmann, Mathias Walzer, Christopher M. Schroeder, Nico Trautwein, Franz J. Hilke, Raphael S. Zinser, Lena Mühlenbruch, Daniel J. Kowalewski, Heiko Schuster, Marc Sturm, Jakob Matthes, Olaf Riess, Stefan Czemmel, Sven Nahnsen, Ingmar Königsrainer, Karolin Thiel, Silvio NadalinStefan Beckert, Hans Bösmüller, Falko Fend, Ana Velic, Boris Maček, Sebastian P. Haen, Luigi Buonaguro, Oliver Kohlbacher, Stefan Stevanović, Alfred Königsrainer, Hans Georg Rammensee, Andrea Mayer-Mokler, Toni Weinschenk, Christian Flohr, Carsten Reinhardt, Harpreet Singh-Jasuja, Roberto S. Accolla, Giovanna Tosi, Greta Forlani, Yuk T. Ma, David Adams, Danila Valmori, Tanguy Chaumette, Regina Heidenreich, Cécile Gouttefangeas, Bruno Sangro, Maria Tagliamonte, Annacarmen Petrizzo, Maria Lina Tornesello, Franco M. Buonaguro

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number28
JournalGenome Medicine
Volume11
Issue number1
DOIs
Publication statusPublished - Apr 30 2019

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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