NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study. Issue 8 (17th November 2018)

• Record Type: Journal Article
• Authors: Cheminant, Morgane; Bruneau, Julie; Malamut, Georgia; Sibon, David; Guegan, Nicolas; van Gils, Tom; Cording, Sascha; Trinquand, Amélie; Verkarre, Virginie; Lhermitte, Ludovic; Brousse, Nicole; Jannot, Anne-Sophie; Khater, Sherine; Frenzel, Laurent; Delarue, Richard; Suarez, Felipe; Marçais, Ambroise; Mulder, Chris JJ; Macintyre, Elizabeth; Asnafi, Vahid; Pouyet, Laurent; Bonnafous, Cécile; Lhospice, Florence; Molina, Thierry Jo; Meresse, Bertrand; Cellier, Christophe; Cerf-Bensussan, Nadine; Hermine, Olivier
• Other Names: author non-byline.; Bouhnik Yoram author non-byline.; Cuenod Charles-andré author non-byline.; Brechignac Sabine author non-byline.; Allez Matthieu author non-byline.; Cosnes Jacques author non-byline.; Fourmestraux Agnès author non-byline.; Delchier Jean-charles author non-byline.; Dupuis Jehan author non-byline.; Haioun Corinne author non-byline.; Gnaoui Taoufik El author non-byline.; Lerebours Eric author non-byline.; Savoye Guillaume author non-byline.; Tilly Herve author non-byline.; Flourie Bernard author non-byline.; Coiffier Bertrand author non-byline.; Hebuterne Xavier author non-byline.; Arab Nadia author non-byline.; Filippi Jérôme author non-byline.; Schneider Stéphane author non-byline.; Zerbib Frank author non-byline.; Milpied Noel author non-byline.; Bouabdallah Krimo author non-byline.; Tabrizi Reza author non-byline.; Vigouroux Stéphane author non-byline.; Pigneux Arnaud author non-byline.; Leguay Thibaut author non-byline.; Dilhuydy Marie-sarah author non-byline.; Dauriac Charles author non-byline.; Bologna Serge author non-byline.; Hulin Cyrille author non-byline.; Bonmati Caroline author non-byline.; Magnin Fréderic author non-byline.; Ranta Dana author non-byline.; Matysiakbudnik Tamara author non-byline.; Deconinck Eric author non-byline.; Pouderoux Philippe author non-byline.; Bonaz Bruno author non-byline.; Gressin Remy author non-byline.; Carbonnel Franck author non-byline.; Gornet Jean-marc author non-byline.; Branche Julien author non-byline.; Saint-georges Georgette author non-byline.; Reimund Jean-marie author non-byline.; Nancey Stéphane author non-byline.; Nachury Maria author non-byline.; Viennot Stéphanie author non-byline.; Zallot Camille author non-byline.; Fabiani Bettina author non-byline.; Marthey Lysiane author non-byline.; Juvin Karine author non-byline.; Baleur Yann Le author non-byline.; Kwiatek Sandy author non-byline.; Saillard Eric author non-byline.; Louvel Dominique author non-byline.; Roblin Xavier author non-byline.; Beau Philippe author non-byline.; Feugier Pierre author non-byline.; Peyrin-biroulet Laurent author non-byline.; Zanaldi Hélène author non-byline.; Brixi-benmansour Hedia author non-byline.; Cadiot Guillaume author non-byline.; Lecomte Thierry author non-byline.; Bretagne Jean-francois author non-byline.; Casasnovas Olivier author non-byline.; Caillot Denis author non-byline.; Bedenne Laurent author non-byline.; Bay Jacques-olivier author non-byline.; Bouteloup Corinne author non-byline.; Duclos Bernard author non-byline.; Foucaud Carine author non-byline.;
• Is Part Of: Gut. Volume 68:Issue 8(2019)
• Page Start: 1396
• Page End: 1405
• Publication Date: 2018-11-17
• Subjects: coeliac disease -- gastrointestinal lymphoma -- tumour markers -- antibody targeted therapy; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2018-317371
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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.