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

Research output: Contribution to journalArticle

75 Citations (Scopus)

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
Externally publishedYes

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T-cells
T-Cell Antigen Receptor
Restoration
Tumors
Lymphoma
B-Lymphocytes
Genes
Chemical activation
T-Lymphocytes
Cells
Receptors, Tumor Necrosis Factor, Member 14
Neoplasms
Antigen Receptors
Germinal Center
Tumor Microenvironment
Pharmacies
Proteins
B-Cell Lymphoma
Helper-Inducer T-Lymphocytes
Cell Communication

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Boice, M., Salloum, D., Mourcin, F., Sanghvi, V., Amin, R., Oricchio, E., ... 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

Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells. / Boice, Michael; Salloum, Darin; Mourcin, Frederic; Sanghvi, Viraj; Amin, Rada; Oricchio, Elisa; Jiang, Man; Mottok, Anja; Denis-Lagache, Nicolas; Ciriello, Giovanni; Tam, Wayne; Teruya-Feldstein, Julie; de Stanchina, Elisa; Chan, Wing C.; Malek, Sami N.; Ennishi, Daisuke; Brentjens, Renier J.; Gascoyne, Randy D.; Cogné, Michel; Tarte, Karin; Wendel, Hans Guido.

In: Cell, Vol. 167, No. 2, 06.10.2016, p. 405-418.e13.

Research output: Contribution to journalArticle

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, WC, Malek, SN, Ennishi, D, Brentjens, RJ, Gascoyne, RD, Cogné, M, Tarte, K & Wendel, HG 2016, 'Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells', Cell, vol. 167, no. 2, pp. 405-418.e13. https://doi.org/10.1016/j.cell.2016.08.032
Boice M, Salloum D, Mourcin F, Sanghvi V, Amin R, Oricchio E et al. Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells. Cell. 2016 Oct 6;167(2):405-418.e13. https://doi.org/10.1016/j.cell.2016.08.032
Boice, Michael ; Salloum, Darin ; Mourcin, Frederic ; Sanghvi, Viraj ; Amin, Rada ; Oricchio, Elisa ; Jiang, Man ; Mottok, Anja ; Denis-Lagache, Nicolas ; Ciriello, Giovanni ; Tam, Wayne ; Teruya-Feldstein, Julie ; de Stanchina, Elisa ; Chan, Wing C. ; Malek, Sami N. ; Ennishi, Daisuke ; Brentjens, Renier J. ; Gascoyne, Randy D. ; Cogné, Michel ; Tarte, Karin ; Wendel, Hans Guido. / Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells. In: Cell. 2016 ; Vol. 167, No. 2. pp. 405-418.e13.
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