NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study
Morgane Cheminant
(1, 2, 3)
,
Julie Bruneau
(3, 4)
,
Georgia Malamut
(5, 3, 2)
,
David Sibon
(4, 2)
,
Nicolas Guegan
(2)
,
Tom van Gils
(6)
,
Sascha Cording
(2)
,
Amélie Trinquand
(7, 8)
,
Virginie Verkarre
(9, 10)
,
Ludovic Lhermitte
(7, 8, 11)
,
Nicole Brousse
(4)
,
Anne-Sophie Jannot
(5)
,
Sherine Khater
(2, 5)
,
Laurent Frenzel
(8, 3, 12)
,
Richard Delarue
(8, 11)
,
Felipe Suarez
(8, 3)
,
Ambroise Marçais
(8, 11)
,
Chris Jj Mulder
(5)
,
Elizabeth Macintyre
(8, 7, 11)
,
Vahid Asnafi
(11, 8, 7)
,
Laurent Pouyet
(13)
,
Cécile Bonnafous
(14)
,
Florence Lhospice
(14)
,
Thierry Jo Molina
(4)
,
Bertrand Meresse
(2, 15)
,
Christophe Cellier
(16, 2)
,
Nadine N. Cerf-Bensussan
(2)
,
Olivier Hermine
(8, 2)
1
Hôpital Necker - Enfants Malades [AP-HP]
2 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
3 ERL 8254 - Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques = Molecular mechanisms of hematological disorders and therapeutic implications
4 Département de Pathologie [CHU Necker]
5 HEGP - Hôpital Européen Georges Pompidou [APHP]
6 VU University Medical Center [Amsterdam]
7 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
8 Service d'immuno-hématologie pédiatrique [CHU Necker]
9 UPD5 Médecine - Université Paris Descartes - Faculté de Médecine
10 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
11 University Paris Descartes Sorbonne Paris Cité, Imagine Institute, Paris
12 University Paris Descartes Sorbonne Paris Cité, Imagine Institute, Paris
13 Mi-mAbs (C/O CIML)
14 Innate Pharma
15 LIRIC - Lille Inflammation Research International Center - U 995
16 Service de gastroenterologie [CHU HEGP]
2 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
3 ERL 8254 - Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques = Molecular mechanisms of hematological disorders and therapeutic implications
4 Département de Pathologie [CHU Necker]
5 HEGP - Hôpital Européen Georges Pompidou [APHP]
6 VU University Medical Center [Amsterdam]
7 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
8 Service d'immuno-hématologie pédiatrique [CHU Necker]
9 UPD5 Médecine - Université Paris Descartes - Faculté de Médecine
10 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
11 University Paris Descartes Sorbonne Paris Cité, Imagine Institute, Paris
12 University Paris Descartes Sorbonne Paris Cité, Imagine Institute, Paris
13 Mi-mAbs (C/O CIML)
14 Innate Pharma
15 LIRIC - Lille Inflammation Research International Center - U 995
16 Service de gastroenterologie [CHU HEGP]
Morgane Cheminant
- Fonction : Auteur
Georgia Malamut
- Fonction : Auteur
Ludovic Lhermitte
- Fonction : Auteur
- PersonId : 771345
- ORCID : 0000-0003-2498-0376
Anne-Sophie Jannot
- Fonction : Auteur
- PersonId : 776949
- IdHAL : anne-sophie-jannot
- ORCID : 0000-0002-8001-8539
- IdRef : 083201297
Laurent Frenzel
- Fonction : Auteur
- PersonId : 762060
- ORCID : 0000-0002-6085-2163
Felipe Suarez
- Fonction : Auteur
- PersonId : 758757
- ORCID : 0000-0002-3537-9052
Nadine N. Cerf-Bensussan
- Fonction : Auteur
- PersonId : 9864
- IdHAL : nadinecerf-bensussan
- ORCID : 0000-0003-0665-1245
- IdRef : 032175221
Olivier Hermine
- Fonction : Auteur
- PersonId : 756140
- ORCID : 0000-0003-2574-3874
- IdRef : 069884927
Résumé
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.