Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.

Détails

ID Serval
serval:BIB_EE618867D6F5
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.
Périodique
Cell
Auteur(s)
Boice M., Salloum D., Mourcin F., Sanghvi V., Amin R., Oricchio E., Jiang M., Mottok A., Denis-Lagache N., Ciriello G., Tam W., Teruya-Feldstein J., de Stanchina E., Chan W.C., Malek S.N., Ennishi D., Brentjens R.J., Gascoyne R.D., Cogné M., Tarte K., Wendel H.G.
ISSN
1097-4172 (Electronic)
ISSN-L
0092-8674
Statut éditorial
Publié
Date de publication
06/10/2016
Peer-reviewed
Oui
Volume
167
Numéro
2
Pages
405-418.e13
Langue
anglais
Notes
Publication types: ARTICLE
Publication Status: ppublish
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't

Résumé
The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas. We report that loss of HVEM leads to cell-autonomous activation of B cell proliferation and drives the development of GC lymphomas in vivo. HVEM-deficient lymphoma B cells also induce a tumor-supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (TFH) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors. Accordingly, administration of the HVEM ectodomain protein (solHVEM((P37-V202))) binds BTLA and restores tumor suppression. To deliver solHVEM to lymphomas in vivo, we engineered CD19-targeted chimeric antigen receptor (CAR) T cells that produce solHVEM locally and continuously. These modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas. Hence, the HVEM-BTLA axis opposes lymphoma development, and our study illustrates the use of CAR-T cells as "micro-pharmacies" able to deliver an anti-cancer protein.

Mots-clé
Adoptive Transfer/methods, Animals, Antigens, CD19/immunology, B-Lymphocytes/immunology, Cell Proliferation, Humans, Lymphocyte Activation, Lymphoma, Follicular/genetics, Lymphoma, Follicular/therapy, Mice, Neoplasms, Experimental/genetics, Neoplasms, Experimental/therapy, Protein Domains, Protein Engineering, Receptors, Immunologic/metabolism, Receptors, Tumor Necrosis Factor, Member 14/chemistry, Receptors, Tumor Necrosis Factor, Member 14/genetics, Receptors, Tumor Necrosis Factor, Member 14/metabolism, Recombinant Fusion Proteins/chemistry, Recombinant Fusion Proteins/genetics, Recombinant Fusion Proteins/metabolism, T-Lymphocytes/immunology, Tumor Microenvironment, Tumor Suppressor Proteins/chemistry, Tumor Suppressor Proteins/genetics, Tumor Suppressor Proteins/metabolism, Xenograft Model Antitumor Assays
Pubmed
Création de la notice
11/10/2016 16:52
Dernière modification de la notice
20/08/2019 16:15
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