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

Michael Boice 1, 2 Darin Salloum 1 Frédéric Mourcin 3, 4 Viraj Sanghvi 1 Rada Amin 3 Elisa Oricchio 5 Man Jiang 1 Anja Mottok 6 Nicolas Denis-Lagache 7, 8 Giovanni Ciriello Wayne Tam Julie Teruya-Feldstein Elisa Stanchina Wing C. Chan Sami N. Malek Daisuke Ennishi Renier J. Brentjens Randy D. Gascoyne Michel Cogné 7 Karin Tarte 3 Hans-Guido Wendel 1
1 Memorial Sloane Kettering Cancer Center [New York]
2 Weill Medical College of Cornell University [New York]
3 MiCa - Microenvironnement et cancer
4 Etablissement Français du Sang Bretagne
5 ISREC - Swiss Institute for Experimental Cancer Research - Lausanne
6 UBC - University of British Columbia
7 CRIBL - Contrôle de la Réponse Immune B et des Lymphoproliférations
8 UNILIM - Université de Limoges
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 (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.
Keywords : transformed follicular lymphoma activation pathogenesis btla b-cells stromal cells cancer-therapy immune regulation inhibitory receptor copy-number
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Journal articles
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01405853
Contributor : Xavier Chard-Hutchinson <>
Submitted on : Wednesday, November 30, 2016 - 3:30:17 PM
Last modification on : Thursday, January 14, 2021 - 11:29:56 AM

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UNIV-RENNES1 | U917 | CNRS | UNILIM | GEIST | BIOSIT | UR1-UFR-SVE | CRBS | CALYM | MICMAC | CRIBL | UNIV-RENNES

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Michael Boice, Darin Salloum, Frédéric Mourcin, Viraj Sanghvi, Rada Amin, et al.. Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells. Cell, Elsevier, 2016, 167 (2), pp.405-418 e13. ⟨10.1016/j.cell.2016.08.032⟩. ⟨hal-01405853⟩

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