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Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors

Nature Medicine volume 17, pages 700–707 (2011)Cite this article

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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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Figure 1: NKp46+ TIL infiltrates in GIST inversely correlate with metastases at diagnosis.
Figure 2: NKp30 splice isoforms mediate different NK cell functions.
Figure 3: NKp30 splice isoforms elicit distinct signals.
Figure 4: Expression of NKp30 isoforms in a cohort of individuals with GIST.
Figure 5: Neutralization of IL-10 restores TH1 cytokine production during the interaction of DC and NK cells from profile-C individuals with GIST.
Figure 6: NKp30 isoform profiles predict the survival of subjects with GIST.

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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/).

Author information

Author notes

  1. Nicolas F Delahaye, Sylvie Rusakiewicz and Isabelle Martins: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut Gustave Roussy (IGR), Villejuif, France

    Nicolas F Delahaye, Sylvie Rusakiewicz, Isabelle Martins, Cédric Ménard, Stephan Roux, Matthieu Sarabi, Nathalie Chaput, Michaela Semeraro, Véronique Minard-Colin, Vichnou Poirier-Colame, Kariman Chaba, Caroline Flament, Dominique Valteau-Couanet, Frédéric Commo, Sylvie Bonvalot, Nicolas Ibrahim, Philippe Terrier, Paule Opolon, Axel Lecesne, Guido Kroemer & Laurence Zitvogel

  2. Institut National de la Santé et de la Recherche Médicale (INSERM), U1015, IGR, Villejuif, France

    Nicolas F Delahaye, Sylvie Rusakiewicz, Cédric Ménard, Stephan Roux, Matthieu Sarabi, Nathalie Chaput, Michaela Semeraro, Véronique Minard-Colin, Kariman Chaba, Caroline Flament, Dominique Valteau-Couanet & Laurence Zitvogel

  3. Center of Clinical Investigations CBT507, IGR, Villejuif, France

    Nicolas F Delahaye, Sylvie Rusakiewicz, Cédric Ménard, Stephan Roux, Matthieu Sarabi, Nathalie Chaput, Vichnou Poirier-Colame, Caroline Flament, Axel Lecesne & Laurence Zitvogel

  4. Université Paris Descartes, Paris, France

    Isabelle Martins, Véronique Baud, Hélène Authier & Guido Kroemer

  5. INSERM, U848, IGR, Villejuif, France

    Isabelle Martins & Guido Kroemer

  6. Metabolomics Platform, IGR, Villejuif, France

    Isabelle Martins & Guido Kroemer

  7. Hematology unit, Hôpital de la Conception, Marseille, France

    Luc Lyonnet & Pascale Paul

  8. Department of Oncological Pediatrics, IGR, Villejuif, France

    Michaela Semeraro, Véronique Minard-Colin & Dominique Valteau-Couanet

  9. INSERM U1016, Institut Cochin, Paris, France

    Véronique Baud & Hélène Authier

  10. Centre National de la Recherche Scientifique, UMR8104, Paris, France

    Véronique Baud & Hélène Authier

  11. Universud, INSERM UMR 996, Faculté de Pharmacie, Châtenay–Malabry, France

    Saadia Kerdine-Römer & Marc Pallardy

  12. INSERM U872, Centre de Recherche des Cordeliers, Paris, France

    Isabelle Cremer

  13. Université Pierre et Marie Curie, UMRS 872, Paris, France

    Isabelle Cremer

  14. INSERM U1020, Paris, France

    Laetitia Peaudecerf & Bénédita Rocha

  15. Faculté de médecine René Descartes, Paris, France

    Laetitia Peaudecerf & Bénédita Rocha

  16. INSERM U891, Centre de Recherche en Cancérologie de Marseille, Marseille, France

    Javier Celis Gutierrez & Jacques A Nunès

  17. Institut Paoli-Calmettes, Marseille, France

    Javier Celis Gutierrez & Jacques A Nunès

  18. Université Méditerranée, Marseille, France

    Javier Celis Gutierrez & Jacques A Nunès

  19. INSERM U981, IGR, Villejuif, France

    Frédéric Commo

  20. Department of Medicine, Sarcoma committee, IGR, Villejuif, France

    Sylvie Bonvalot, Philippe Terrier & Axel Lecesne

  21. Department of Pathology, IGR, Villejuif, France

    Nicolas Ibrahim & Philippe Terrier

  22. Experimental Pathology Unit of IGR, Villejuif, France

    Paule Opolon

  23. Université Paris XI, Faculté de Médecine Paris-Sud, Kremlin-Bicêtre, France

    Paule Opolon & Laurence Zitvogel

  24. Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy

    Cristina Bottino & Alessandro Moretta

  25. Istituto Giannina Gaslini, Genoa, Italy

    Cristina Bottino

  26. Department of Medical Protein Research, Faculty of Medicine and Health, Ghent University, Ghent, Belgium

    Jan Tavernier

  27. Flanders Interuniversity Institute for Biotechnology, Ghent University, Ghent, Belgium

    Jan Tavernier

  28. TAGC INSERM, U928, Aix-Marseille université, Marseille, France

    Pascal Rihet

  29. Department of Pathology, InstitutBergonié, Bordeaux, France

    Jean-Michel Coindre

  30. Department of Medicine, Centre Léon-Bérard, Lyon, France

    Jean-Yves Blay

  31. Department of Oncology, Centre Georges-François Leclerc, Dijon, France

    Nicolas Isambert

  32. INSERM CIC-P 803, Dijon, France

    Nicolas Isambert

  33. Department of Pathology, EA4340, Hôpital Ambroise Paré, Boulogne, France

    Jean-François Emile

  34. Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Marseille, France

    Eric Vivier

  35. Institut National de la Santé et de la Recherche Médicale, U631, Marseille, France

    Eric Vivier

  36. Centre National de la Recherche Scientifique, UnitéMixte de Recherche 6102, Marseille, France

    Eric Vivier

  37. Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France

    Eric Vivier

  38. Centre de Recherche des Cordeliers, Paris, France

    Guido Kroemer

  39. Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France

    Guido Kroemer

Authors
  1. Nicolas F Delahaye
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Contributions

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.

Corresponding authors

Correspondence to Guido Kroemer or Laurence Zitvogel.

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The authors declare no competing financial interests.

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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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