<br>纤维板层肝细胞癌中基于肽的免疫疗法可以特异性靶向致癌融合蛋白 DNAJB1-PRKACA,Nature Communications

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纤维板层肝细胞癌中基于肽的免疫疗法可以特异性靶向致癌融合蛋白 DNAJB1-PRKACA
Nature Communications ( IF 14.7 ) Pub Date : 2022-10-27 , 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 _{1,

2,

3,

10,

12}

Affiliation

Department of Peptide-based Immunotherapy, University and University Hospital Tübingen, Tübingen, Germany.
Department of Immunology, Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.
Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany.
CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
Department of Pediatric Hematology and Oncology, University Children's Hospital, University of Tübingen, Tübingen, Germany.
Faculty of Biology, Albert-Ludwigs-Universität, Freiburg, Germany.
Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Quantitative Biology Center (QBiC), University of Tübingen, Tübingen, Germany.
Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.
Department of Otorhinolaryngology, Head and Neck Surgery, University of Tübingen, Tübingen, Germany.
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tübingen, Tübingen, Germany.
Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany.
Department of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany.
Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Partner Site, Freiburg, Germany.
Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany.

DNAJB1-PRKACA 融合转录本是纤维板层肝细胞癌的致癌驱动因素，纤维板层肝细胞癌是一种缺乏特异性治疗的致命疾病。本研究报告了纤维板层肝细胞癌中 DNAJB1-PRKACA 融合转录物特异的 HLA 呈递新抗原的鉴定、表征和免疫治疗应用。 DNAJB1-PRKACA 衍生的 HLA I 类和 HLA II 类配体诱导多功能细胞毒性 CD8 ⁺和 T 辅助细胞 1 CD4 ⁺ T 细胞，并且通过基于质谱的免疫肽组分析证明了它们在表达 DNAJB1-PRKACA 的肿瘤细胞中的细胞加工和呈递。单细胞 RNA 测序进一步从 DNAJB1-PRKACA 特异性 T 细胞中鉴定出多种 T 细胞受体。患有复发性短间隔疾病复发的纤维板层肝细胞癌患者在持续聚（ADP-核糖）聚合酶抑制剂治疗下接种 DNAJB1-PRKACA 衍生肽可诱导多功能 CD4 ⁺ T 细胞，具有激活的 T 辅助细胞 1 表型和高 T 细胞受体克隆性。疫苗诱导的 DNAJB1-PRKACA 特异性 T 细胞反应会随着时间的推移而持续存在，并且与之前的各种治疗相反，伴随着患者在接种疫苗后 21 个月以上的持久无复发生存。我们的临床前和临床研究结果确定 DNAJB1-PRKACA 蛋白是免疫原性新表位和相应 T 细胞受体的来源，并为专门针对这种致癌融合的基于 T 细胞的免疫疗法的单患者研究提供了功效。

"点击查看英文标题和摘要"

The 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 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.

更新日期：2022-10-27

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