期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-33746-3
关键词
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资金
- Deutsche Forschungsgemeinschaft [EXC2180-390900677, 390939984]
- German Cancer Consortium (DKTK)
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [WA4608/1-2, 259373024/Z01, 256073931/Z02, 431984000/S1, 441891347/S1, 441891347]
- Wilhelm Sander Stiftung [2016.177.3]
- Jose Carreras Leukamie-Stiftung [DJCLS 05R/2017]
- Bundesministerium fur Bildung und Forschung (BMBF) [FKZ:01KI20130, FKZ:16LW0005, FKZ:01DP21014, FKZ 01ZZ1801B]
- Else Kroner Fresenius Stiftung, Translatorik Programm [2022_EKTP03]
- Deutsche Krebshilfe (German Cancer Aid) [70114948]
- Zentren fur Personalisierte Medizin
- Applied Clinical Research program
- Fortune Program of the University of Tubingen [2451-0-0]
The DNAJB1-PRKACA fusion protein is identified as a source of immunogenic neoepitopes and a potential target for T cell-based immunotherapy in fibrolamellar hepatocellular carcinoma. Vaccination with DNAJB1-PRKACA-derived peptides induces long-lasting T cell responses and improves survival in a single-patient study.
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. 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.
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