title: NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients.
abstract: Despite effective targeted therapy acting onKITandPDGFRAtyrosine 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 (ΔBClow) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This ΔBClowblood 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.
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rusakiewicz
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Perier
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Department of Pediatric Oncology, GRCC, Villejuif, France.
authors.forename: Michaela
authors.initials: M
authors.lastname: Semeraro
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Pitt
authors.affiliation: Department of Internal Medicine I, University Hospital of Cologne , Cologne, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Pogge von Strandmann
authors.affiliation: Department of Internal Medicine I, University Hospital of Cologne , Cologne, Germany.
authors.forename: Katrin S
authors.initials: KS
authors.lastname: Reiners
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Drug Development Department (DITEP), GRCC, Villejuif, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Aspeslagh
authors.affiliation: Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille , Marseille, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Pipéroglou
authors.affiliation: Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France; INSERM, U1104, Centre d'Immunologie de Marseille-Luminy, Marseille, France; CNRS, UMR7280, Marseille, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Vély
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Ivagnes
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jegou
authors.affiliation: Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, Heidelberg, Germany; National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Halama
authors.affiliation: Department of Medical Oncology, Centre Hospitalier Universitaire Jean Minjoz , Besançon, France.
authors.forename: Loic
authors.initials: L
authors.lastname: Chaigneau
authors.affiliation: Department of Pathology, Institut Mutualiste Montsouris, Paris, France; Department of Medical Oncology, Sarcoma, Institut Mutualiste Montsouris, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Validire
authors.affiliation: Department of Medical Oncology, Sarcoma, Institut Mutualiste Montsouris, Paris, France; Department of Surgery, Institut Mutualiste Montsouris, University of Paris Descartes 5, Paris, France.
authors.forename: Christos
authors.initials: C
authors.lastname: Christidis
authors.affiliation: Department of Medical Oncology, Sarcoma, Institut Mutualiste Montsouris , Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Perniceni
authors.affiliation: Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, University of Paris Descartes 5 , Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Landi
authors.affiliation: Department of Surgery, Georges Pompidou European Hospital, University of Paris Descartes , Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Berger
authors.affiliation: Department of Medical Oncology, Centre Georges-François Leclerc , Dijon, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Isambert
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medicine, Sarcoma committee, GRCC, Villejuif, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Domont
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medicine, Sarcoma committee, GRCC, Villejuif, France; Department of Surgery, GRCC, Villejuif, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bonvalot
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medicine, Sarcoma committee, GRCC, Villejuif, France; Department of Pathology, GRCC, Villejuif, France; Center of Biological Resources, GRCC, Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Terrier
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Pathology, GRCC, Villejuif, France; Center of Biological Resources, GRCC, Villejuif, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Adam
authors.affiliation: Department of Pathology, Institut Bergonié , Bordeaux, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.affiliation: Department of Pathology, EA4340, Hôpital Ambroise Paré , Boulogne, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France.
authors.forename: Vichnou
authors.initials: V
authors.lastname: Poirier-Colame
authors.affiliation: Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM, U1138, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France.
authors.forename: Kariman
authors.initials: K
authors.lastname: Chaba
authors.affiliation: INSERM, U1020, Paris, France; Faculté de Médecine René Descartes, Paris, France.
authors.forename: Benedita
authors.initials: B
authors.lastname: Rocha
authors.affiliation: INSERM, U1160, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Groupe Hospitalier Saint Louis-Lariboisière - F. Vidal, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Caignard
authors.affiliation: INSERM, U1160, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Groupe Hospitalier Saint Louis-Lariboisière - F. Vidal, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Toubert
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM, U1138, Paris, France; Metabolomics and Cell Biology platforms, GRCC, Villejuif, France.
authors.forename: David
authors.initials: D
authors.lastname: Enot
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Mainz Medical Centre , Mainz, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Koch
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Drug Development Department (DITEP), GRCC, Villejuif, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Marabelle
authors.affiliation: INSERM, U1149, Equipe "Immunité innée chez l'enfant", Hôpital Robert Debré , Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Lambert
authors.affiliation: INSERM, U1149, Equipe "Immunité innée chez l'enfant", Hôpital Robert Debré , Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Caillat-Zucman
authors.affiliation: Department of Oncology, University Hospital , Lausanne, Switzerland.
authors.forename: Serge
authors.initials: S
authors.lastname: Leyvraz
authors.affiliation: Applied Biology and Pharmacology Laboratory, Ecole Normale Supèrieur of Cachan , Cachan, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Auclair
authors.affiliation: INSERM, U1104, Centre d'Immunologie de Marseille-Luminy, Marseille, France; CNRS, UMR7280, Marseille, France; Aix Marseille Université, UM2, Marseille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.affiliation: Gustave Roussy Cancer Campus (GRCC) , Villejuif, France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggermont
authors.affiliation: INSERM 1098, University of Franche-Comté , Besançon, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Borg
authors.affiliation: Department of Medicine, Centre Léon Bérard & Université Claude Bernard Lyon I, DGOS-INCA SIRIC , Lyon, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medicine, Sarcoma committee, GRCC, Villejuif, France.
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medicine, Sarcoma committee, GRCC, Villejuif, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Mir
authors.affiliation: Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France; University of Paris Sud XI, Villejuif, France.
authors.forename: Laurence
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authors.lastname: Zitvogel
keywords: B7-H6; Cancer; GIST; NK cells; NKp30/NCR3; immunity