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 - Funding Information:
We thank Irina Linkov (Memorial Sloan-Kettering Cancer Center [MSKCC]), Shenqiu Wang (MSKCC), Ana Ortega-Molina (MSKCC), and Sylvain Prigent (Rennes University) for advice and reagents. Thanks to all the members of MSK Antitumor assessment core for technical assistance with mice; the MSK Laboratory of Comparative Pathology, MSK Flow Cytometry, MSK Molecular Cytology, and Microscopy Rennes Imaging Center (MRic-ALMF); and UMS 6480 cores and thanks to the Centre de Ressources Biologiques (CRB)-Santé (BB-0033-00056) of Rennes hospital for its support in the processing of biological samples. This research was supported by funding from the American Cancer Society grant RSG-13-048-01-LIB (H.-G.W.), the Lymphoma Research Foundation (H.-G.W.), Cycle for Survival (H.-G.W.), the Steven A. Greenberg Foundation, Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, and The Center for Experimental Therapeutics at MSKCC (H.-G.W.), NIH grants RO1CA183876-03, 1RO1CA207217-01, and 1R01CA19038-01 (H.-G.W.), Core Grant P30 CA008748 (H.-G.W.), NIH Spore P50 CA192937-01A1, LLS Score GC227931 (H.-G.W.), LLS 1318-15 (H.-G.W.), the Ligue Nationale contre le Cancer (K.T.), the Foundation ARC pour la recherche sur le cancer (AO 2011), the French Institut National du Cancer (INCA AAP PLBIO-13-085; K.T.), the Follicular lymphoma grant from Lymphoma Research Foundation (W.C.C.), NIH grant 1R01CA190384-01 (S.N.M.), NIH grants R01CA138738-05, PO1CA059350, and PO1CA190174-01 (R.J.B.). A.M. is supported by the Dr. Mildred-Scheel Cancer Foundation (Deutsche Krebshilfe), The Michael Smith Foundation for Health Research, and Lymphoma Canda; S.N.M. is a Scholar of the Leukemia and Lymphoma Society; H.-G.W. is a Scholar of the Leukemia and Lymphoma Society. R.A. is supported by the FEDER (Fonds Européens de Développement Régional), the CPER (Contrat de plan Etat région Bretagne, axe biothérapie), and the ADHO (Association pour le Développement de l’Hémato-Oncologie).
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.
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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 -
