Low mutational load in pediatric medulloblastoma still translates into neoantigens as targets for specific T-cell immunotherapy

Blaeschke, Franziska; Paul, Milan Cedric; Schuhmann, Martin Ulrich; Rabsteyn, Armin; Schröder, Christopher; Casadei, Nicolas; Matthes, Jakob; Mohr, Christopher; Lotfi, Ramin; Wagner, Beate; Kaeuferle, Theresa; Feucht, Judith; Willier, Semjon; Handgretinger, Rupert; Stevanovic, Stefan; Lang, Peter und Feuchtinger, Tobias (2019): Low mutational load in pediatric medulloblastoma still translates into neoantigens as targets for specific T-cell immunotherapy. In: Cytotherapy, Bd. 21, Nr. 9: S. 973-986

Abstract

Background: Medulloblastoma is the most common malignant brain tumor in childhood and adolescence. Although some patients present with distinct genetic alterations, such as mutated TP53 or MYC amplification, pediatric medulloblastoma is a tumor entity with minimal mutational load and low immunogenicity. Methods: We identified tumor-specific mutations using next-generation sequencing of medulloblastoma DNA and RNA derived from primary tumor samples from pediatric patients. Tumor-specific mutations were confirmed using deep sequencing and in silico analyses predicted high binding affinity of the neoantigen-derived peptides to the patients' human leukocyte antigen molecules. Tumor-specific peptides were synthesized and used to induce a de novo T-cell response characterized by interferon gamma and tumor necrosis factor alpha release of CD8(+) cytotoxic T cells in vitro. Results: Despite low mutational tumor burden, at least two immunogenic tumorspecific peptides were identified in each patient. T cells showed a balanced CD4/CD8 ratio and mostly effector memory phenotype. Induction of a CD8-specific T-cell response was achieved for the neoepitopes derived from Histidine Ammonia-Lyase (HAL), Neuraminidase 2 (NEU2), Proprotein Convertase Subtilisin (PCSK9), Programmed Cell Death 10 (PDCD10), Supervillin (SVIL) and tRNA Splicing Endonuclease Subunit 54 (TSEN54) variants. Conclusion: Detection of patient-specific, tumor-derived neoantigens confirms that even in tumors with low mutational load a molecular design of targets for specific T-cell immunotherapy is possible. The identified neoantigens may guide future approaches of adoptive T-cell transfer, transgenic T-cell receptor transfer or tumor vaccination.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1465-3249
• Sprache: Englisch