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.

journal_name

Cell

journal_title

Cell

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 WC,Malek SN,Ennishi D,Brentjens RJ,Gascoyne RD,Cogné M,Tarte K,Wende

doi

10.1016/j.cell.2016.08.032

subject

Has Abstract

pub_date

2016-10-06 00:00:00

pages

405-418.e13

issue

2

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(16)31083-2

journal_volume

167

pub_type

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