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.
- coeliac disease
- gastrointestinal lymphoma
- tumour markers
- antibody targeted therapy
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CC, NC-B and OH contributed equally.
MC, JB and GM contributed equally.
Contributors MC, JB, GM, OH and NC-B conceptualised, supervised the study and wrote the manuscript. MC, JB, NG, TvG, SC provided data and data analysis. A-SJ, MC contributed to statistical interpretation. MC, JB, GM, CC, NG, DS, TvG, CJJM, RD, FS, AM, LF, SK, BM, TJM, VA, EM, VA, LP, AT, NB provided patient material and clinical data. MC, JB and OH obtained fundings. All authors edited and approved the final version of the paper. MC, NC-B and OH were responsible for the final version of the manuscript.
Funding The study was financially supported by Institut National de la Santé et de la Recherche Médicale (INSERM), Innate Pharma (Marseille, France), Institut national du cancer (INCA), la ligue contre le cancer, l’association pour la recherche contre le cancer (ARC), l’agence nationale de la recherche (ANR) and Université Paris Diderot. MC is a recipient of grant from INCA.
Competing interests FL and CB are senior directors and have ownership interest (including patents) in Innate Pharma. MC, JB and OH received research grants from Innate Pharma.
Patient consent Not required.
Ethics approval Ile-de-France Ethics Committee II.
Provenance and peer review Not commissioned; externally peer reviewed.
Collaborators CELAC Network : Yoram Bouhnik, Charles-André Cuenod, Sabine Brechignac, Matthieu Allez, Jacques Cosnes, Agnès Fourmestraux, Jean-Charles Delchier, Jehan Dupuis, Corinne Haioun, Taoufik El Gnaoui, Eric Lerebours, Guillaume Savoye, Herve Tilly, Bernard Flourie, Bertrand Coiffier, Xavier Hebuterne, Nadia Arab, Jérôme Filippi, Stéphane Schneider, Frank Zerbib, Noel Milpied, Krimo Bouabdallah, Reza Tabrizi, Stéphane Vigouroux, Arnaud Pigneux, Thibaut Leguay, Marie-Sarah Dilhuydy, Charles Dauriac, Serge Bologna, Cyrille Hulin, Caroline Bonmati, Fréderic Magnin, Dana Ranta, Tamara Matysiakbudnik, Eric Deconinck, Philippe Pouderoux, Bruno Bonaz, Remy Gressin, Franck Carbonnel, Jean-Marc Gornet, Julien Branche, Georgette Saint-Georges, Jean-Marie Reimund, Stéphane Nancey, Maria Nachury, Stéphanie Viennot, Camille Zallot, Bettina Fabiani, Lysiane Marthey, Karine Juvin, Yann Le Baleur, Sandy Kwiatek, Eric Saillard, Dominique Louvel, Xavier Roblin, Philippe Beau, Pierre Feugier, Laurent Peyrin-Biroulet, Hélène Zanaldi, Hedia Brixi-Benmansour, Guillaume Cadiot, Thierry Lecomte, Jean-Francois Bretagne, Olivier Casasnovas, Denis Caillot, Laurent Bedenne, Jacques-Olivier Bay, Corinne Bouteloup, Bernard Duclos, Carine Foucaud.