[HTML][HTML] Loss of the HVEM tumor suppressor in lymphoma and restoration by modified CAR-T cells

M Boice, D Salloum, F Mourcin, V Sanghvi, R Amin… - Cell, 2016 - cell.com
M Boice, D Salloum, F Mourcin, V Sanghvi, R Amin, E Oricchio, M Jiang, A Mottok…
Cell, 2016cell.com
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 …
Summary
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.
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