Research Papers:

Natural killer cells facilitate PRAME-specific T-cell reactivity against neuroblastoma

Lotte Spel _, Jaap-Jan Boelens, Dirk M. van der Steen, Nina J.G. Blokland, Max M. van Noesel, Jan J. Molenaar, Mirjam H.M. Heemskerk, Marianne Boes and Stefan Nierkens

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Oncotarget. 2015; 6:35770-35781. https://doi.org/10.18632/oncotarget.5657

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Lotte Spel1, Jaap-Jan Boelens1,2, Dirk M. van der Steen3, Nina J.G. Blokland1, Max M. van Noesel4, Jan J. Molenaar5, Mirjam H.M. Heemskerk3, Marianne Boes1,6,*, Stefan Nierkens1,*

1Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

2Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands

3Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

4Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands

5Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

6Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

*These authors have contributed equally to this work

Correspondence to:

Stefan Nierkens, e-mail: [email protected]

Marianne Boes, e-mail: [email protected]

Keywords: class I MHC, immune evasion, PRAME, neuroblastoma, immunotherapy

Received: July 16, 2015     Accepted: September 24, 2015     Published: October 06, 2015


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.

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