(1) Rusakiewicz S (2) Perier A (3) Semeraro M (4) Pitt JM (5) Pogge von Strandmann E (6) Reiners KS (7) Aspeslagh S (8) Piperoglou C (9) Vely F (10) Ivagnes A (11) Jegou S (12) Halama N (13) Chaigneau L (14) Validire P (15) Christidis C (16) Perniceni T (17) Landi B (18) Berger A (19) Isambert N (20) Domont J (21) Bonvalot S (22) Terrier P (23) Adam J (24) Coindre JM (25) Emile JF (26) Poirier-Colame V (27) Chaba K (28) Rocha B (29) Caignard A (30) Toubert A (31) Enot D (32) Koch J (33) Marabelle A (34) Lambert M (35) Caillat-Zucman S (36) Leyvraz S (37) Auclair C (38) Vivier E (39) Eggermont A (40) Borg C (41) Blay JY (42) Le Cesne A (43) Mir O (44) Zitvogel L

Oncoimmunology

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 (DeltaBClow) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This DeltaBClow 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-alpha and anti-TRAIL mAb which reinstated innate immunity.

Author Info: (1) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, F

Author Info: (1) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France. (2) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France. (3) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Department of Pediatric Oncology, GRCC, Villejuif, France. (4) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France. (5) Department of Internal Medicine I, University Hospital of Cologne , Cologne, Germany. (6) Department of Internal Medicine I, University Hospital of Cologne , Cologne, Germany. (7) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Drug Development Department (DITEP), GRCC, Villejuif, France. (8) Hopital de la Conception, Assistance Publique-Hopitaux de Marseille , Marseille, France. (9) Hopital de la Conception, Assistance Publique-Hopitaux de Marseille, Marseille, France; INSERM, U1104, Centre d'Immunologie de Marseille-Luminy, Marseille, France; CNRS, UMR7280, Marseille, France. (10) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France. (11) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France. (12) Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, Heidelberg, Germany; National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. (13) Department of Medical Oncology, Centre Hospitalier Universitaire Jean Minjoz , Besancon, France. (14) Department of Pathology, Institut Mutualiste Montsouris, Paris, France; Department of Medical Oncology, Sarcoma, Institut Mutualiste Montsouris, Paris, France. (15) Department of Medical Oncology, Sarcoma, Institut Mutualiste Montsouris, Paris, France; Department of Surgery, Institut Mutualiste Montsouris, University of Paris Descartes 5, Paris, France. (16) Department of Medical Oncology, Sarcoma, Institut Mutualiste Montsouris , Paris, France. (17) Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, University of Paris Descartes 5 , Paris, France. (18) Department of Surgery, Georges Pompidou European Hospital, University of Paris Descartes , Paris, France. (19) Department of Medical Oncology, Centre Georges-Francois Leclerc , Dijon, France. (20) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medicine, Sarcoma committee, GRCC, Villejuif, France. (21) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medicine, Sarcoma committee, GRCC, Villejuif, France; Department of Surgery, GRCC, Villejuif, France. (22) 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. (23) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Pathology, GRCC, Villejuif, France; Center of Biological Resources, GRCC, Villejuif, France. (24) Department of Pathology, Institut Bergonie , Bordeaux, France. (25) Department of Pathology, EA4340, Hopital Ambroise Pare , Boulogne, France. (26) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France. (27) Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM, U1138, Paris, France; Universite Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. (28) INSERM, U1020, Paris, France; Faculte de Medecine Rene Descartes, Paris, France. (29) INSERM, U1160, Universite Paris Diderot, Sorbonne Paris Cite, Paris, France; Groupe Hospitalier Saint Louis-Lariboisiere - F. Vidal, Paris, France. (30) INSERM, U1160, Universite Paris Diderot, Sorbonne Paris Cite, Paris, France; Groupe Hospitalier Saint Louis-Lariboisiere - F. Vidal, Paris, France. (31) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Equipe 11 labellisee 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. (32) Institute of Medical Microbiology and Hygiene, University of Mainz Medical Centre , Mainz, Germany. (33) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Drug Development Department (DITEP), GRCC, Villejuif, France. (34) INSERM, U1149, Equipe "Immunite innee chez l'enfant", Hopital Robert Debre , Paris, France. (35) INSERM, U1149, Equipe "Immunite innee chez l'enfant", Hopital Robert Debre , Paris, France. (36) Department of Oncology, University Hospital , Lausanne, Switzerland. (37) Applied Biology and Pharmacology Laboratory, Ecole Normale Superieur of Cachan , Cachan, France. (38) INSERM, U1104, Centre d'Immunologie de Marseille-Luminy, Marseille, France; CNRS, UMR7280, Marseille, France; Aix Marseille Universite, UM2, Marseille, France. (39) Gustave Roussy Cancer Campus (GRCC) , Villejuif, France. (40) INSERM 1098, University of Franche-Comte , Besancon, France. (41) Department of Medicine, Centre Leon Berard & Universite Claude Bernard Lyon I, DGOS-INCA SIRIC , Lyon, France. (42) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medicine, Sarcoma committee, GRCC, Villejuif, France. (43) Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medicine, Sarcoma committee, GRCC, Villejuif, France. (44) 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.

Citation: Oncoimmunology 2017 6:e1137418 Epub04/25/2016

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/28197361

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