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

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 - HEPAVAC Consortium

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 - Aged

KW - Aged, 80 and over

KW - Antigens, Neoplasm/genetics

KW - Carcinoma, Hepatocellular/genetics

KW - Exome

KW - Female

KW - Genomics/methods

KW - Humans

KW - Liver Neoplasms/genetics

KW - Male

KW - Middle Aged

KW - Mutation Rate

KW - Transcriptome

U2 - 10.1186/s13073-019-0636-8

DO - 10.1186/s13073-019-0636-8

M3 - SCORING: Journal article

C2 - 31039795

VL - 11

SP - 28

JO - GENOME MED

JF - GENOME MED

SN - 1756-994X

IS - 1

ER -