Neuroblastoma is the most common solid tumor in children, with mortality rates after conventional treatments still being 80% for high-risk (stage 4) disease. There is a clear medical need for development of new treatment strategies. Recently, immunotherapy has gained traction. However, restrained MHC I expression evades recognition of neuroblastoma by immune cells, for a suppressed immunogenic status of neuroblastoma tumors. We here describe a preclinical study aimed to improve neuroblastoma immunogenicity. We found that neuroblastoma cells significantly increase surface expression of MHC I upon exposure to active NK cells and thereby readily sensitize neuroblastoma cells for recognition by cytotoxic T lymphocytes (CTLs). We show that oncoprotein PRAME serves as a T-cell antigen in neuroblastoma as NK-modulated neuroblastoma cells are recognized by PRAMESLLQHLIGL/A2-specific CTL clones. Furthermore, NK cell induced MHC I upregulation in neuroblastoma cells requires IFNγ production by NK cells that is triggered by neuroblastoma contact. Our results demonstrate remarkable plasticity in the immunogenic properties of neuroblastoma cells, which are exposed when neuroblastoma cells attempt to escape innate immune attack. These findings support the exploration of NK cells in combined immunotherapy to enforce tumor-specific CTL responses, and thereby strengthen immune-mediated tumor reactivity.
Citation Format: Lotte Spel, Jaap J. Boelens, Niek van Til, Dirk M. van der Steen, Nina J.G. Blokland, Max M. van Noesel, Jan J. Molenaar, Mirjam H.M. Heemskerk, Marianne Boes, Stefan Nierkens. Improved CD8+ T-cell recognition of neuroblastoma after innate immune attack by natural killer cells. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B037.
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