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

Sylvie Rusakiewicz; Aurélie Perier; Michaela Semeraro; Jonathan M. Pitt; Elke Pogge von Strandmann; Katrin S. Reiners; Sandrine Aspeslagh; Christelle Pipéroglou; Frédéric Vély; Alexandre Ivagnes; Sarah Jegou; Niels Halama; Loic Chaigneau; Pierre Validire; Christos Christidis; Thierry Perniceni; Bruno Landi; Anne Berger; Nicolas Isambert; Julien Domont; Sylvie Bonvalot; Philippe Terrier; Julien Adam; Jean Michel Coindre; Jean François Emile; Vichnou Poirier-Colame; Kariman Chaba; Benedita Rocha; Anne Caignard; Antoine Toubert; David Enot; Joachim Koch; Aurélien Marabelle; Marion Lambert; Sophie Caillat Zucman; Serge Leyvraz; Christian Auclair; Eric Vivier; Alexander Eggermont; Christophe Borg; Jean Yves Blay; Axel Le Cesne; Olivier Mir; Laurence Zitvogela

doi:10.1080/2162402X.2015.1137418

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

Sylvie Rusakiewicz, Aurélie Perier, Michaela Semeraro, Jonathan M. Pitt, Elke Pogge von Strandmann, Katrin S. Reiners, Sandrine Aspeslagh, Christelle Pipéroglou, Frédéric Vély, Alexandre Ivagnes, Sarah Jegou, Niels Halama, Loic Chaigneau, Pierre Validire, Christos Christidis, Thierry Perniceni, Bruno Landi, Anne Berger, Nicolas Isambert, Julien DomontSylvie Bonvalot, Philippe Terrier, Julien Adam, Jean Michel Coindre, Jean François Emile, Vichnou Poirier-Colame, Kariman Chaba, Benedita Rocha, Anne Caignard, Antoine Toubert, David Enot, Joachim Koch, Aurélien Marabelle, Marion Lambert, Sophie Caillat Zucman, Serge Leyvraz, Christian Auclair, Eric Vivier, Alexander Eggermont, Christophe Borg, Jean Yves Blay, Axel Le Cesne, Olivier Mir, Laurence Zitvogela

Research output: Contribution to journal › Article › peer-review

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

Original language	English
Article number	e1137418
Journal	OncoImmunology
Volume	6
Issue number	1
DOIs	https://doi.org/10.1080/2162402X.2015.1137418
Publication status	Published - 2 Jan 2017

Keywords

B7-H6
Cancer
GIST
Immunity
NK cells
NKp30/NCR3

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10.1080/2162402X.2015.1137418

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Rusakiewicz, S., Perier, A., Semeraro, M., Pitt, J. M., von Strandmann, E. P., Reiners, K. S., Aspeslagh, S., Pipéroglou, C., Vély, F., Ivagnes, A., Jegou, S., Halama, N., Chaigneau, L., Validire, P., Christidis, C., Perniceni, T., Landi, B., Berger, A., Isambert, N., ... Zitvogela, L. (2017). NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients. OncoImmunology, 6(1), Article e1137418. https://doi.org/10.1080/2162402X.2015.1137418

@article{d05db8a470d1410384413fe2fffa015e,

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

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

keywords = "B7-H6, Cancer, GIST, Immunity, NK cells, NKp30/NCR3",

author = "Sylvie Rusakiewicz and Aur{\'e}lie Perier and Michaela Semeraro and Pitt, \{Jonathan M.\} and \{von Strandmann\}, \{Elke Pogge\} and Reiners, \{Katrin S.\} and Sandrine Aspeslagh and Christelle Pip{\'e}roglou and Fr{\'e}d{\'e}ric V{\'e}ly and Alexandre Ivagnes and Sarah Jegou and Niels Halama and Loic Chaigneau and Pierre Validire and Christos Christidis and Thierry Perniceni and Bruno Landi and Anne Berger and Nicolas Isambert and Julien Domont and Sylvie Bonvalot and Philippe Terrier and Julien Adam and Coindre, \{Jean Michel\} and Emile, \{Jean Fran{\c c}ois\} and Vichnou Poirier-Colame and Kariman Chaba and Benedita Rocha and Anne Caignard and Antoine Toubert and David Enot and Joachim Koch and Aur{\'e}lien Marabelle and Marion Lambert and Zucman, \{Sophie Caillat\} and Serge Leyvraz and Christian Auclair and Eric Vivier and Alexander Eggermont and Christophe Borg and Blay, \{Jean Yves\} and Cesne, \{Axel Le\} and Olivier Mir and Laurence Zitvogela",

note = "Publisher Copyright: {\textcopyright} 2017 Taylor \& Francis Group, LLC.",

year = "2017",

month = jan,

day = "2",

doi = "10.1080/2162402X.2015.1137418",

language = "English",

volume = "6",

journal = "OncoImmunology",

issn = "2162-4011",

number = "1",

}

Rusakiewicz, S, Perier, A, Semeraro, M, Pitt, JM, von Strandmann, EP, Reiners, KS, Aspeslagh, S, Pipéroglou, C, Vély, F, Ivagnes, A, Jegou, S, Halama, N, Chaigneau, L, Validire, P, Christidis, C, Perniceni, T, Landi, B, Berger, A, Isambert, N, Domont, J, Bonvalot, S, Terrier, P, Adam, J, Coindre, JM, Emile, JF, Poirier-Colame, V, Chaba, K, Rocha, B, Caignard, A, Toubert, A, Enot, D, Koch, J, Marabelle, A, Lambert, M, Zucman, SC, Leyvraz, S, Auclair, C, Vivier, E, Eggermont, A, Borg, C, Blay, JY, Cesne, AL, Mir, O & Zitvogela, L 2017, 'NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients', OncoImmunology, vol. 6, no. 1, e1137418. https://doi.org/10.1080/2162402X.2015.1137418

TY - JOUR

T1 - NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients

AU - Rusakiewicz, Sylvie

AU - Perier, Aurélie

AU - Semeraro, Michaela

AU - Pitt, Jonathan M.

AU - von Strandmann, Elke Pogge

AU - Reiners, Katrin S.

AU - Aspeslagh, Sandrine

AU - Pipéroglou, Christelle

AU - Vély, Frédéric

AU - Ivagnes, Alexandre

AU - Jegou, Sarah

AU - Halama, Niels

AU - Chaigneau, Loic

AU - Validire, Pierre

AU - Christidis, Christos

AU - Perniceni, Thierry

AU - Landi, Bruno

AU - Berger, Anne

AU - Isambert, Nicolas

AU - Domont, Julien

AU - Bonvalot, Sylvie

AU - Terrier, Philippe

AU - Adam, Julien

AU - Coindre, Jean Michel

AU - Emile, Jean François

AU - Poirier-Colame, Vichnou

AU - Chaba, Kariman

AU - Rocha, Benedita

AU - Caignard, Anne

AU - Toubert, Antoine

AU - Enot, David

AU - Koch, Joachim

AU - Marabelle, Aurélien

AU - Lambert, Marion

AU - Zucman, Sophie Caillat

AU - Leyvraz, Serge

AU - Auclair, Christian

AU - Vivier, Eric

AU - Eggermont, Alexander

AU - Borg, Christophe

AU - Blay, Jean Yves

AU - Cesne, Axel Le

AU - Mir, Olivier

AU - Zitvogela, Laurence

PY - 2017/1/2

Y1 - 2017/1/2

N2 - 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 (ΔBClow) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This ΔBClow 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.

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

KW - B7-H6

KW - Cancer

KW - GIST

KW - Immunity

KW - NK cells

KW - NKp30/NCR3

UR - http://www.scopus.com/inward/record.url?scp=85020486355&partnerID=8YFLogxK

U2 - 10.1080/2162402X.2015.1137418

DO - 10.1080/2162402X.2015.1137418

M3 - Article

C2 - 28197361

AN - SCOPUS:85020486355

SN - 2162-4011

VL - 6

JO - OncoImmunology

JF - OncoImmunology

IS - 1

M1 - e1137418

ER -

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

Abstract

Keywords

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