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

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Boice, Michael | Salloum, Darin | Mourcin, Frédéric | Sanghvi, Viraj | Amin, Rada | Oricchio, Elisa | Jiang, Man | Mottok, Anja | Denis-Lagache, Nicolas | Ciriello, Giovanni | Tam, Wayne | Teruya-Feldstein, Julie | Stanchina, Elisa, De | Chan, Wing C. | Malek, Sami N. | Ennishi, Daisuke | Brentjens, Renier J. | Gascoyne, Randy D. | Cogné, Michel | Tarte, Karin | Wendel, Hans-Guido

Edité par CCSD ; Elsevier -

International audience. 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 (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.

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