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      NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients

      research-article
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      Oncoimmunology
      Taylor & Francis
      Cancer, immunity, B7-H6, GIST, NK cells, NKp30/NCR3

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          ABSTRACT

          Despite effective targeted therapy acting on KIT and PDGFRA tyrosine kinases, gastrointestinal stromal tumors (GIST) escape treatment by acquiring mutations conveying resistance to imatinib mesylate (IM). Following the identification of NKp30-based immunosurveillance of GIST and the off-target effects of IM on NK cell functions, we investigated the predictive value of NKp30 isoforms and NKp30 soluble ligands in blood for the clinical response to IM. The relative expression and the proportions of NKp30 isoforms markedly impacted both event-free and overall survival, in two independent cohorts of metastatic GIST. Phenotypes based on disbalanced NKp30B/NKp30C ratio (ΔBC low) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This ΔBC low blood phenotype was associated with a pro-inflammatory and immunosuppressive tumor microenvironment. In addition, detectable levels of the NKp30 ligand sB7-H6 predicted a worse prognosis in metastatic GIST. Soluble BAG6, an alternate ligand for NKp30 was associated with low NKp30 transcription and had additional predictive value in GIST patients with high NKp30 expression. Such GIST microenvironments could be rescued by therapy based on rIFN-α and anti-TRAIL mAb which reinstated innate immunity.

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          Author and article information

          Journal
          Oncoimmunology
          Oncoimmunology
          KONI
          koni20
          Oncoimmunology
          Taylor & Francis
          2162-4011
          2162-402X
          2017
          25 April 2016
          : 6
          : 1
          Affiliations
          [a ] Gustave Roussy Cancer Campus (GRCC) , Villejuif, France
          [b ] INSERM, U1015, IGR , Villejuif, France
          [c ] Center of Clinical Investigations in Biotherapies of Cancer (CICBT) , Villejuif, France
          [d ] Department of Pediatric Oncology, GRCC , Villejuif, France
          [e ] Department of Internal Medicine I, University Hospital of Cologne , Cologne, Germany
          [f ] Drug Development Department (DITEP), GRCC , Villejuif, France
          [g ] Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille , Marseille, France
          [h ] INSERM, U1104, Centre d'Immunologie de Marseille-Luminy , Marseille, France
          [i ] CNRS, UMR7280 , Marseille, France
          [j ] Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT , Heidelberg, Germany
          [k ] National Center for Tumor Diseases, University Hospital Heidelberg , Heidelberg, Germany
          [l ] Department of Medical Oncology, Centre Hospitalier Universitaire Jean Minjoz , Besançon, France
          [m ] Department of Pathology, Institut Mutualiste Montsouris , Paris, France
          [n ] Department of Medical Oncology, Sarcoma, Institut Mutualiste Montsouris , Paris, France
          [o ] Department of Surgery, Institut Mutualiste Montsouris, University of Paris Descartes 5 , Paris, France
          [p ] Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, University of Paris Descartes 5 , Paris, France
          [q ] Department of Surgery, Georges Pompidou European Hospital, University of Paris Descartes , Paris, France
          [r ] Department of Medical Oncology, Centre Georges-François Leclerc , Dijon, France
          [s ] Department of Medicine, Sarcoma committee, GRCC , Villejuif, France
          [t ] Department of Surgery, GRCC , Villejuif, France
          [u ] Department of Pathology, GRCC , Villejuif, France
          [v ] Center of Biological Resources, GRCC , Villejuif, France
          [w ] Department of Pathology, Institut Bergonié , Bordeaux, France
          [x ] Department of Pathology, EA4340, Hôpital Ambroise Paré , Boulogne, France
          [y ] Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers , Paris, France
          [z ] INSERM, U1138 , Paris, France
          [aa ] Université Paris Descartes/Paris V, Sorbonne Paris Cité , Paris, France
          [ab ] INSERM, U1020 , Paris, France
          [ac ] Faculté de Médecine René Descartes , Paris, France
          [ad ] INSERM, U1160, Université Paris Diderot, Sorbonne Paris Cité , Paris, France
          [ae ] Groupe Hospitalier Saint Louis-Lariboisière - F. Vidal , Paris, France
          [af ] Metabolomics and Cell Biology platforms, GRCC , Villejuif, France
          [ag ] Institute of Medical Microbiology and Hygiene, University of Mainz Medical Centre , Mainz, Germany
          [ah ] INSERM, U1149, Equipe “Immunité innée chez l'enfant”, Hôpital Robert Debré , Paris, France
          [ai ] Department of Oncology, University Hospital , Lausanne, Switzerland
          [aj ] Applied Biology and Pharmacology Laboratory, Ecole Normale Supèrieur of Cachan , Cachan, France
          [ak ] INSERM, U1104, Centre d'Immunologie de Marseille-Luminy , Marseille, France
          [al ] CNRS, UMR7280 , Marseille, France
          [am ] Aix Marseille Université, UM2 , Marseille, France
          [an ] INSERM 1098, University of Franche-Comté , Besançon, France
          [ao ] Department of Medicine, Centre Léon Bérard & Université Claude Bernard Lyon I, DGOS-INCA SIRIC , Lyon, France
          [ap ] University of Paris Sud XI , Villejuif, France
          Author notes
          CONTACT Pr Laurence Zitvogel laurence.zitvogel@ 123456gustaveroussy.fr

          Supplemental material data for this article can be accessed on the publisher's website.

          Article
          PMC5283614 PMC5283614 5283614 1137418
          10.1080/2162402X.2015.1137418
          5283614
          28197361
          db3a6828-e13e-46b3-96ed-acf8a7b106e7
          © 2017 Taylor & Francis Group, LLC
          Page count
          Figures: 6, Tables: 1, References: 42, Pages: 13
          Categories
          Original Research

          NKp30/NCR3,Cancer,immunity,B7-H6,GIST,NK cells
          NKp30/NCR3, Cancer, immunity, B7-H6, GIST, NK cells

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