| Literature DB >> 27693350 |
Michael Boice1, Darin Salloum2, Frederic Mourcin3, Viraj Sanghvi2, Rada Amin3, Elisa Oricchio4, Man Jiang2, Anja Mottok5, Nicolas Denis-Lagache6, Giovanni Ciriello7, Wayne Tam8, Julie Teruya-Feldstein9, Elisa de Stanchina10, Wing C Chan11, Sami N Malek12, Daisuke Ennishi5, Renier J Brentjens13, Randy D Gascoyne5, Michel Cogné6, Karin Tarte14, Hans-Guido Wendel15.
Abstract
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.Entities:
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Year: 2016 PMID： 27693350 PMCID： PMC5221752 DOI： 10.1016/j.cell.2016.08.032
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582