title: Natural killer cells facilitate PRAME-specific T-cell reactivity against neuroblastoma.
abstract: Neuroblastoma is the most common solid tumor in children with an estimated 5-year progression free survival of 20-40% in stage 4 disease. Neuroblastoma actively avoids recognition by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Although immunotherapy has gained traction for neuroblastoma treatment, these immune escape mechanisms restrain clinical results. Therefore, we aimed to improve neuroblastoma immunogenicity to further the development of antigen-specific immunotherapy against neuroblastoma. We found that neuroblastoma cells significantly increase surface expression of MHC I upon exposure to active NK cells which thereby readily sensitize neuroblastoma cells for recognition by CTLs. We show that oncoprotein PRAME serves as an immunodominant antigen for neuroblastoma as NK-modulated neuroblastoma cells are recognized by PRAMESLLQHLIGL/A2-specific CTL clones. Furthermore, NK cells induce MHC I upregulation in neuroblastoma through contact-dependent secretion of IFNγ. Our results demonstrate remarkable plasticity in the peptide/MHC I surface expression of neuroblastoma cells, which is reversed when neuroblastoma cells experience innate immune attack by sensitized NK cells. These findings support the exploration of NK cells as adjuvant therapy to enforce neuroblastoma-specific CTL responses.
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Lotte
authors.initials: L
authors.lastname: Spel
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.|Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jaap-Jan
authors.initials: JJ
authors.lastname: Boelens
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: van der Steen
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Nina J G
authors.initials: NJ
authors.lastname: Blokland
authors.affiliation: Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors.forename: Max M
authors.initials: MM
authors.lastname: van Noesel
authors.affiliation: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Molenaar
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Mirjam H M
authors.initials: MH
authors.lastname: Heemskerk
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: Boes
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Nierkens
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D019496:Cancer Vaccines; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D016056:Immunodominant Epitopes / Q000378:metabolism; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D009447:Neuroblastoma / Q000276:immunology / Q000628:therapy*; D010446:Peptide Fragments / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; C404944:PRAME protein, human; D010446:Peptide Fragments; D007371:Interferon-gamma
keywords: PRAME; class I MHC; immune evasion; immunotherapy; neuroblastoma