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

Sylvie Rusakiewicz (1) , Aurelie Perier , Michaela Semeraro (2, 1) , Jonathan M. Pitt (3, 4, 1, 5) , Elke Pogge Von Strandmann , Katrin S. Reiners , Sandrine Aspeslagh (6) , Christelle Piperoglou (7, 8) , Frederic Vely (9, 8) , Alexandre Ivagnes (1) , Sarah Jegou (10, 11) , Niels Halama , Loic Chaigneau (12) , Pierre Validire (13) , Christos Christidis (14) , Thierry Perniceni (15) , Bruno Landi (16) , Anne Berger , Nicolas Isambert (17, 18) , Julien Domont (19) , Sylvie Bonvalot , Philippe Terrier (20) , Julien Adam (21, 20) , Jean-Michel Coindre (22) , Jean-Francois Emile (23) , Vichnou Poirier-Colame (1) , Kariman Chaba (24) , Benedita Rocha (25, 26) , Anne Caignard (27, 28) , Antoine Toubert (27) , David Enot (3, 29) , Joachim Koch (30) , Aurelien Marabelle (6) , Marion Lambert , Sophie Caillat-Zucman (31, 32) , Serge Leyvraz , Christian Auclair (33) , Eric Vivier (8) , Alexander Eggermont (3) , Christophe Borg (12) , Jean-Yves Blay (34) , Axel Le Cesne (35) , Olivier Mir (35) , Laurence Zitvogel (3, 1, 36, 37)

1 UMR 1015 - Immunologie des tumeurs et immunothérapie
2 CHU Necker - Enfants Malades [AP-HP]
3 IGR - Institut Gustave Roussy
4 UP11 UFR Médecine - Université Paris-Sud - Paris 11 - Faculté de médecine
5 Université Paris-Saclay
6 DITEP - Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy]
7 Laboratoire d'Immunologie [Hôpital de la Conception - APHM]
8 CIML - Centre d'Immunologie de Marseille - Luminy
9 Service d'Immunologie [AP-HM]
10 LBM-E4 - Microorganismes, Molécules Bioactives et Physiopathologie Intestinale
11 Service de rhumatologie [CHU Saint-Antoine]
12 Service d'Oncologie Médicale [CHRU Besançon]
13 Departement d'Anatomopathologie
14 Hellenic Open University [Patras]
15 Département de chirurgie digestive
16 HEGP - Hôpital Européen Georges Pompidou [APHP]
17 LabEx LipSTIC - Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer
18 Département d'oncologie médicale [Centre Georges-François Leclerc]
19 Centre Jean-bernard
20 Département de biologie et pathologie médicales [Gustave Roussy]
21 U981 - Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse
22 Service de Pathologie
23 Service de pathologie [CHU Ambroise Paré]
24 CRC - Inserm U1138 - Immunologie et Cancérologie Intégratives
25 U1020 - Différenciation et physiologie des lymphocytes T
26 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
27 A2T - Alloimmunité-Autoimmunité-Transplantation
28 IUH - Institut Universitaire d'Hématologie
29 Plateforme de métabolomique
30 University Medical Centre of the Johannes Gutenberg University Mainz
31 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
32 Laboratoire d'immunologie
33 LBPA - Laboratoire de Biologie et de Pharmacologie Appliquée
34 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
35 Département de médecine oncologique [Gustave Roussy]
36 AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)
37 CIC 1428 , CBT 507 - Centre d'Investigation Clinique en Biotherapie des cancers

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 (Delta BClow) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This Delta BClow 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.

Domains: Life Sciences [q-bio]; Immunology

Sylvie Rusakiewicz, Aurelie Perier, Michaela Semeraro, Jonathan M. Pitt, Elke Pogge Von Strandmann, et al.. NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients. OncoImmunology, 2017, 6 (1), ⟨10.1080/2162402X.2015.1137418⟩. ⟨hal-01765085⟩