biostudies-literatureBauer JDeutsche ForschungsgemeinschaftWilhelm Sander-StiftungDeutsche KrebshilfeJosé Carreras Leukämie-StiftungElse Kröner-Fresenius-Stiftung6401https://www.ebi.ac.uk/biostudies/studies/S-EPMC9613889biostudies-literatureUnknown13(1)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 fibrolaNature communicationsThe oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma.PMC9613889EXC2180 390900677DJCLS 05 R/2017701149482016.177.32022_EKTP03Bilich TBrecht IBMaringer YDicks SKohler NDenk MRichter MSchroeder SHailfinger SBauer JHolzer UBonzheim IFeucht JBitzer MBoerries MWalz JSKlein RWacker MBucher PSalih HRScheid JRammensee HGLuibrand JZwick MNelde ADubbelaar MEbinger MRieth JHeitmann JSfalseThe oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma.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 fibrola2022-01-01T00:00:00Z2022 Oct2026-05-28T03:35:36.025Z2024-11-12T07:53:12.493ZS-EPMC96138893630275410.1038/s41467-022-33746-3