NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: A CELAC study

Morgane Cheminant, Julie Bruneau, Georgia Malamut, David Sibon, Nicolas Guegan, Tom van Gils, Sascha Cording, Amélie Trinquand, Virginie Verkarre, Ludovic Lhermitte, Nicole Brousse, Anne-Sophie Jannot, Sherine Khater, Laurent Frenzel, Richard Delarue, Felipe Suarez, Ambroise Marçais, Chris J. J. Mulder, Elizabeth Macintyre, Vahid AsnafiLaurent Pouyet, C. cile Bonnafous, Florence Lhospice, Thierry Jo Molina, Bertrand Meresse, Christophe Cellier, Nadine Cerf-Bensussan, Olivier Hermine

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41 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)1396-1405
Issue number8
Early online date2018
Publication statusPublished - 1 Aug 2019

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