Loss of the HVEM tumor suppressor in lymphoma and restoration by modified CAR-T cells Journal Article

Authors: 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.; Tarte, K.; Wendel, H. G.
Article Title: Loss of the HVEM tumor suppressor in lymphoma and restoration by modified CAR-T cells
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. © 2016 Elsevier Inc.
Journal Title: Cell
Volume: 167
Issue: 2
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2016-10-06
Start Page: 405
End Page: 418.e13
Language: English
DOI: 10.1016/j.cell.2016.08.032
PROVIDER: scopus
PUBMED: 27693350
PMCID: PMC5221752
Notes: Article -- Export Date: 2 November 2016 -- Source: Scopus
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MSK Authors
  1. Renier J Brentjens
    199 Brentjens
  2. Hans Guido Wendel
    60 Wendel
  3. Man Jiang
    12 Jiang
  4. Michael   Boice
    5 Boice