TY - JOUR
T1 - Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells
AU - Boice, Michael
AU - Salloum, Darin
AU - Mourcin, Frederic
AU - Sanghvi, Viraj
AU - Amin, Rada
AU - Oricchio, Elisa
AU - Jiang, Man
AU - Mottok, Anja
AU - Denis-Lagache, Nicolas
AU - Ciriello, Giovanni
AU - Tam, Wayne
AU - Teruya-Feldstein, Julie
AU - de Stanchina, Elisa
AU - Chan, Wing C.
AU - Malek, Sami N.
AU - Ennishi, Daisuke
AU - Brentjens, Renier J.
AU - Gascoyne, Randy D.
AU - Cogné, Michel
AU - Tarte, Karin
AU - Wendel, Hans Guido
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/10/6
Y1 - 2016/10/6
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84990857167
U2 - 10.1016/j.cell.2016.08.032
DO - 10.1016/j.cell.2016.08.032
M3 - Article
C2 - 27693350
AN - SCOPUS:84990857167
SN - 0092-8674
VL - 167
SP - 405-418.e13
JO - Cell
JF - Cell
IS - 2
ER -