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

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

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33746-3

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