TY - JOUR
T1 - Multi-omics discovery of exome-derived neoantigens in hepatocellular carcinoma
AU - Löffler, Markus W.
AU - Mohr, Christopher
AU - Bichmann, Leon
AU - Freudenmann, Lena Katharina
AU - Walzer, Mathias
AU - Schroeder, Christopher M.
AU - Trautwein, Nico
AU - Hilke, Franz J.
AU - Zinser, Raphael S.
AU - Mühlenbruch, Lena
AU - Kowalewski, Daniel J.
AU - Schuster, Heiko
AU - Sturm, Marc
AU - Matthes, Jakob
AU - Riess, Olaf
AU - Czemmel, Stefan
AU - Nahnsen, Sven
AU - Königsrainer, Ingmar
AU - Thiel, Karolin
AU - Nadalin, Silvio
AU - Beckert, Stefan
AU - Bösmüller, Hans
AU - Fend, Falko
AU - Velic, Ana
AU - Maček, Boris
AU - Haen, Sebastian P.
AU - Buonaguro, Luigi
AU - Kohlbacher, Oliver
AU - Stevanović, Stefan
AU - Königsrainer, Alfred
AU - Rammensee, Hans Georg
AU - Mayer-Mokler, Andrea
AU - Weinschenk, Toni
AU - Flohr, Christian
AU - Reinhardt, Carsten
AU - Singh-Jasuja, Harpreet
AU - Accolla, Roberto S.
AU - Tosi, Giovanna
AU - Forlani, Greta
AU - Ma, Yuk T.
AU - Adams, David
AU - Valmori, Danila
AU - Chaumette, Tanguy
AU - Heidenreich, Regina
AU - Gouttefangeas, Cécile
AU - Sangro, Bruno
AU - Tagliamonte, Maria
AU - Petrizzo, Annacarmen
AU - Tornesello, Maria Lina
AU - Buonaguro, Franco M.
PY - 2019/4/30
Y1 - 2019/4/30
N2 - 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.
AB - 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.
KW - Hepatocellular carcinoma
KW - HLA
KW - HLA ligandomics
KW - Immunoinformatics
KW - Immunotherapy
KW - Liver cancer
KW - Mass spectrometry
KW - Multi-omics
KW - Neoantigen
KW - Next-generation sequencing
KW - Peptide prediction
KW - Personalized medicine
UR - http://www.scopus.com/inward/record.url?scp=85065126856&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065126856&partnerID=8YFLogxK
U2 - 10.1186/s13073-019-0636-8
DO - 10.1186/s13073-019-0636-8
M3 - Article
AN - SCOPUS:85065126856
VL - 11
JO - Genome Medicine
JF - Genome Medicine
SN - 1756-994X
IS - 1
M1 - 28
ER -