TY - JOUR
T1 - Natural killer cells facilitate PRAME-specific T-cell reactivity against neuroblastoma
AU - Spel, Lotte
AU - Boelens, Jaap-Jan
AU - van der Steen, Dirk M
AU - Blokland, Nina J G
AU - van Noesel, Max M
AU - Molenaar, Jan J
AU - Heemskerk, Mirjam H M
AU - Boes, Marianne
AU - Nierkens, Stefan
PY - 2015/10
Y1 - 2015/10
N2 - 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.
AB - 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.
KW - Antigens, Neoplasm/metabolism
KW - Cancer Vaccines
KW - Cells, Cultured
KW - Gene Expression Regulation, Neoplastic
KW - HLA-A2 Antigen/metabolism
KW - Humans
KW - Immunity, Innate
KW - Immunodominant Epitopes/metabolism
KW - Immunotherapy, Adoptive
KW - Interferon-gamma/metabolism
KW - Killer Cells, Natural/immunology
KW - Neuroblastoma/immunology
KW - Peptide Fragments/metabolism
KW - T-Lymphocytes, Cytotoxic/immunology
KW - Tumor Escape
UR - http://www.scopus.com/inward/record.url?scp=84946822326&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.5657
DO - 10.18632/oncotarget.5657
M3 - Article
C2 - 26452036
SN - 1949-2553
VL - 6
SP - 35770
EP - 35781
JO - Oncotarget
JF - Oncotarget
IS - 34
ER -