Boice, MichaelSalloum, DarinMourcin, FredericSanghvi, VirajAmin, RadaOricchio, ElisaJiang, ManMottok, AnjaDenis-Lagache, NicolasCiriello, GiovanniTam, WayneTeruya-Feldstein, JulieDe Stanchina, ElisaChan, Wing C.Malek, Sami N.Ennishi, DaisukeBrentjens, Renier J.Gascoyne, Randy D.Cogne, MichelTarte, KarinWendel, Hans-Guido2016-11-212016-11-212016-11-21201610.1016/j.cell.2016.08.032https://infoscience.epfl.ch/handle/20.500.14299/131403WOS:000386343100017The 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 (T-FH) 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.text::journal::journal article::research article