Abstract
The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3′ untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.
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Acknowledgements
We thank P. Anderson for providing the CD3ζ-specific antibody (2H2 clone), M. Baratin for helpful discussions and the affected subjects as well as the healthy volunteers for their kind participation. U848 and U1015 are supported by Ligue contre le Cancer (équipes labellisées), Fondation pour la Recherche Médicale, European Union (Apo-Sys, ArtForce, ChemoRes, INFLACARE), INCa ('NKp30' in 2006; 'NCR3 isoforms' in 2008), Agence Nationale de la Recherche and Fondation de France (2009–2011). N.F.D. was supported by Institut National du Cancer and Fondation Gustave Roussy. S. Rusakiewicz was supported by a studentship from the Fondation pour la Recherche Médicale. V.B. was supported by the Ligue contre le Cancer, Agence Nationale de la Recherche, Association pour la Recherche contre le Cancer, Belgian Interuniversity Attraction Pole, Cancéropole Ile-de-France and Université Paris Descartes. J.C.G. was supported by the Fundayacucho-CNOUS joint program. Some materials and data used in this study were provided by the conticagist (https://www.conticagist.org/).
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N.F.D., S. Ruskiewicz, I.M., C.M., S. Roux, N.C., M. Sarabi, C.F., M. Semeraro, V.P.-C. and K.C. performed the experiments. L.L. and P.P. did qRT-PCRs. V.M.-C. and D.V.-C. contributed to clinical aspects of the study. V.B. and H.A. performed the electrophoretic mobility shift assays. S.K.-R. and M.P. provided the p38 MAP kinase inhibitors and scientific advice. I.C. contributed to the NKp46 immunohistochemistry study. L.P. and B.R. performed single-cell RT-PCRs. C.B. and A.M. provided the NK cell clones and the NKp30 and NKp44 antibodies. J.C.G., J.A.N. and J.T. contributed to exploration of the MAP kinase pathway. F.C. contributed to the statistical analysis. N. Ibrahim, P.T. and P.O. provided the paraffin-embedded GIST specimens and monitored histopathology data. S.B., J.-M.C., J.-Y.B., N. Isambert and A.L. provided samples from affected individuals and clinical data. J.-F.E. identified the KIT mutations in the affected-subject cohort. P.R. contributed to genotyping of the NCR3 mutations. E.V. provided the B7H6 antibody and scientific advice. N.F.D., S. Rusakiewicz and I.M. prepared the figures and drafted the manuscript. G.K. and L.Z. designed the study and wrote the manuscript.
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Delahaye, N., Rusakiewicz, S., Martins, I. et al. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat Med 17, 700–707 (2011). https://doi.org/10.1038/nm.2366
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DOI: https://doi.org/10.1038/nm.2366
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