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

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

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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.

Original languageEnglish
Pages (from-to)405-418.e13
JournalCell
Volume167
Issue number2
DOIs
Publication statusPublished - Oct 6 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    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., ... Wendel, H. G. (2016). Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells. Cell, 167(2), 405-418.e13. https://doi.org/10.1016/j.cell.2016.08.032