Journal Article

The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma

Ebinger, Martin, Luibrand, Julia, Bitzer, Michael, Boerries, Melanie, Bonzheim, Irina, Walz, Juliane S., Wacker, Marcel, Bucher, Philip, Scheid, Jonas, Rammensee, Hans-Georg, Bilich, Tatjana, Dicks, Severin, Dubbelaar, Marissa, Brecht, Ines B., Rieth, Jonas, Nelde, Annika, Bauer, Jens, Zwick, Melissa, Heitmann, Jonas S., Feucht, Judith, Denk, Monika, Salih, Helmut R., Schroeder, Sarah, Köhler, Natalie, Richter, Marion, Hailfinger, Stephan, Klein, Reinhild, Maringer, Yacine, Holzer, Ursula

2022

Overview

The DNAJB1-PRKACA fusion transcript is the oncogenic driver in fibrolamellar hepatocellular carcinoma, a lethal disease lacking specific therapies. This study reports on the identification, characterization, and immunotherapeutic application of HLA-presented neoantigens specific for the DNAJB1-PRKACA fusion transcript in fibrolamellar hepatocellular carcinoma. DNAJB1-PRKACA-derived HLA class I and HLA class II ligands induce multifunctional cytotoxic CD8 + and T-helper 1 CD4 + T cells, and their cellular processing and presentation in DNAJB1-PRKACA expressing tumor cells is demonstrated by mass spectrometry-based immunopeptidome analysis. Single-cell RNA sequencing further identifies multiple T cell receptors from DNAJB1-PRKACA-specific T cells. Vaccination of a fibrolamellar hepatocellular carcinoma patient, suffering from recurrent short interval disease relapses, with DNAJB1-PRKACA-derived peptides under continued Poly (ADP-ribose) polymerase inhibitor therapy induces multifunctional CD4 + T cells, with an activated T-helper 1 phenotype and high T cell receptor clonality. Vaccine-induced DNAJB1-PRKACA-specific T cell responses persist over time and, in contrast to various previous treatments, are accompanied by durable relapse free survival of the patient for more than 21 months post vaccination. Our preclinical and clinical findings identify the DNAJB1-PRKACA protein as source for immunogenic neoepitopes and corresponding T cell receptors and provide efficacy in a single-patient study of T cell-based immunotherapy specifically targeting this oncogenic fusion. The DNAJB1-PRKACA fusion transcript is the oncogenic driver in fibrolamellar hepatocellular carcinoma, a lethal disease with limited therapeutic options. Here, the authors identify the DNAJB1-PRKACA protein as a source for immunogenic neoepitopes and a potential target of T cell-based immunotherapy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 45/91 / 631/67/1059/2325 / 631/67/1504/1610 / 82/58 / Adenosine diphosphate / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - pathology / Carcinoma, Hepatocellular - therapy / CD4 antigen / CD8 antigen / Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Cytotoxicity / Fusion protein / Gene Expression Regulation, Neoplastic / Gene sequencing / Hepatocellular carcinoma / Histocompatibility antigen HLA / HSP40 Heat-Shock Proteins - genetics / Humanities and Social Sciences / Humans / Immunization / Immunogenicity / Immunotherapy / Liver cancer / Liver Neoplasms - genetics / Liver Neoplasms - pathology / Liver Neoplasms - therapy / Lymphocytes / Lymphocytes T / Mass spectrometry / Mass spectroscopy / multidisciplinary / Neoantigens / Neoplasm Recurrence, Local - genetics / Oncogene Proteins, Fusion - genetics / Patients / Peptides / Peptides - genetics / Phenotypes / Proteins / Receptors / Ribose / Science / Science (multidisciplinary) / T cell receptors / Tumor cells / Vaccination / Vaccines