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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 
10 LBM-E4 - Microorganismes, Molécules Bioactives et Physiopathologie Intestinale
UPMC - Université Pierre et Marie Curie - Paris 6, INSERM - Institut National de la Santé et de la Recherche Médicale : U1057
24 CRC - Inserm U1138 - Immunologie et Cancérologie Intégratives
CRC - Centre de Recherche des Cordeliers
29 Plateforme de métabolomique
Direction de la recherche [Gustave Roussy]
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 (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.
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Submitted on : Thursday, April 12, 2018 - 3:38:26 PM
Last modification on : Monday, November 28, 2022 - 10:38:07 AM

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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⟩



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