RT Journal Article
SR Electronic
T1 NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1396
OP 1405
DO 10.1136/gutjnl-2018-317371
VO 68
IS 8
A1 Morgane Cheminant
A1 Julie Bruneau
A1 Georgia Malamut
A1 David Sibon
A1 Nicolas Guegan
A1 Tom van Gils
A1 Sascha Cording
A1 Amélie Trinquand
A1 Virginie Verkarre
A1 Ludovic Lhermitte
A1 Nicole Brousse
A1 Anne-Sophie Jannot
A1 Sherine Khater
A1 Laurent Frenzel
A1 Richard Delarue
A1 Felipe Suarez
A1 Ambroise Marçais
A1 Chris JJ Mulder
A1 Elizabeth Macintyre
A1 Vahid Asnafi
A1 Laurent Pouyet
A1 Cécile Bonnafous
A1 Florence Lhospice
A1 Thierry Jo Molina
A1 Bertrand Meresse
A1 Christophe Cellier
A1 Nadine Cerf-Bensussan
A1 Olivier Hermine
A1 ,
YR 2019
UL http://gut.bmj.com/content/68/8/1396.abstract
AB Objectives Primary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs).Design NKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD). NKp46 was next assessed by immunohistochemistry in paraffin-embedded biopsies from 204 patients with CD, RCDI, RCDII or GI T-cell lymphomas and from a validation cohort of 61 patients. The cytotoxic properties of an anti-NKp46 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) was tested ex vivo in human primary tumour cells isolated from fresh duodenal biopsies.Results NKp46 (but not CD94, NKG2A, NKG2C, NKG2D) was significantly more expressed by malignant RCDII IEL than by normal IEL in CD and RCDI. In paraffin biopsies, detection of >25 NKp46+ IEL per 100 epithelial cells discriminated RCDII from CD and RCDI. NKp46 was also detected in enteropathy-associated T-cell lymphomas (EATL, 24/29) and in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, 4/4) but not in indolent T-LPD (0/15). Treatment with anti-NKp46-PBD could efficiently and selectively kill human NKp46+ primary IEL ex vivo.Conclusion NKp46 is a novel biomarker useful for diagnosis and therapeutic stratification of GI T-LPD. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.