NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study.
Cheminant M, Bruneau J, Malamut G, Sibon D, Guegan N, van Gils T, Cording S, Trinquand A, Verkarre V, Lhermitte L, Brousse N, Jannot AS, Khater S, Frenzel L, Delarue R, Suarez F, Marçais A, Mulder CJ, Macintyre E, Asnafi V, Pouyet L, Bonnafous C, Lhospice F, Molina TJ, Meresse B, Cellier C, Cerf-Bensussan N, Hermine O, Bouhnik Y, Cuenod CA, Brechignac S, Allez M, Cosnes J, Fourmestraux A, Delchier JC, Dupuis J, Haioun C, Gnaoui TE, Lerebours E, Savoye G, Tilly H, Flourie B, Coiffier B, Hebuterne X, Arab N, Filippi J, Schneider S, Zerbib F, Milpied N, Bouabdallah K, Tabrizi R, Vigouroux S, Pigneux A, Leguay T, Dilhuydy MS, Dauriac C, Bologna S, Hulin C, Bonmati C, Magnin F, Ranta D, Matysiakbudnik T, Deconinck E, Pouderoux P, Bonaz B, Gressin R, Carbonnel F, Gornet JM, Branche J, Saint-Georges G, Reimund JM, Nancey S, Nachury M, Viennot S, Zallot C, Fabiani B, Marthey L, Juvin K, Baleur YL, Kwiatek S, Saillard E, Louvel D, Roblin X, Beau P, Feugier P, Peyrin-Biroulet L, Zanaldi H, Brixi-Benmansour H, Cadiot G, Lecomte T, Bretagne JF, Casasnovas O, Caillot D, Bedenne L, Bay JO, Bouteloup C, Duclos B, Foucaud C.
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Abstract
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.