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

Nat Commun. 2022 Oct 27;13(1):6401. doi: 10.1038/s41467-022-33746-3.

Jens Bauer ¹ ² ³, Natalie Köhler ⁴ ⁵, Yacine Maringer ¹ ² ³, Philip Bucher ³ ⁶, Tatjana Bilich ¹ ² ³, Melissa Zwick ⁴ ⁷, Severin Dicks ⁷ ⁸, Annika Nelde ¹ ² ³, Marissa Dubbelaar ¹ ² ³ ⁹, Jonas Scheid ¹ ² ⁹, Marcel Wacker ¹ ² ³, Jonas S Heitmann ³ ¹⁰, Sarah Schroeder ¹ ² ¹¹, Jonas Rieth ¹ ², Monika Denk ¹ ² ¹², Marion Richter ¹ ² ¹², Reinhild Klein ¹³, Irina Bonzheim ¹⁴, Julia Luibrand ¹⁴, Ursula Holzer ⁶, Martin Ebinger ⁶, Ines B Brecht ⁶, Michael Bitzer ³ ¹² ¹⁵, Melanie Boerries ⁸ ¹⁶, Judith Feucht ³ ⁶, Helmut R Salih ³ ¹⁰, Hans-Georg Rammensee ² ³ ¹², Stephan Hailfinger ³ ¹⁷, Juliane S Walz ¹⁸ ¹⁹ ²⁰ ²¹ ²²

Affiliations

1 Department of Peptide-based Immunotherapy, University and University Hospital Tübingen, Tübingen, Germany.
2 Department of Immunology, Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
3 Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.
4 Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany.
5 CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
6 Department of Pediatric Hematology and Oncology, University Children's Hospital, University of Tübingen, Tübingen, Germany.
7 Faculty of Biology, Albert-Ludwigs-Universität, Freiburg, Germany.
8 Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
9 Quantitative Biology Center (QBiC), University of Tübingen, Tübingen, Germany.
10 Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.
11 Department of Otorhinolaryngology, Head and Neck Surgery, University of Tübingen, Tübingen, Germany.
12 German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tübingen, Tübingen, Germany.
13 Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany.
14 Department of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany.
15 Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.
16 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Partner Site, Freiburg, Germany.
17 Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany.
18 Department of Peptide-based Immunotherapy, University and University Hospital Tübingen, Tübingen, Germany. [email protected].
19 Department of Immunology, Institute for Cell Biology, University of Tübingen, Tübingen, Germany. [email protected].
20 Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany. [email protected].
21 Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany. [email protected].
22 German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tübingen, Tübingen, Germany. [email protected].

PMID: 36302754 DOI: 10.1038/s41467-022-33746-3

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.