Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.
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.
Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
Michael
M
Boice
Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Darin
D
Salloum
INSERM U917, Equipe labellisée Ligue contre le Cancer, Université Rennes 1, EFS Bretagne, CHU Rennes, 35000 Rennes, France.
Frederic
F
Mourcin
Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Viraj
V
Sanghvi
INSERM U917, Equipe labellisée Ligue contre le Cancer, Université Rennes 1, EFS Bretagne, CHU Rennes, 35000 Rennes, France.
Rada
R
Amin
Swiss Institute for Cancer Research (ISREC), EPFL SV-Batiment 19, 1003 Lausanne, Switzerland.
Elisa
E
Oricchio
Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Man
M
Jiang
Centre for Lymphoid Cancer, British Columbia Cancer Agency and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
Anja
A
Mottok
Centre National de la Recherche Scientifque, UMR 7276, Université de Limoges, 8700 Limoges, France.
Nicolas
N
Denis-Lagache
Department of Computational Biology, University of Lausanne, Rue du Bugnon 27, 1005 Lausanne, Switzerland; The Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
Giovanni
G
Ciriello
Department of Pathology and Laboratory Medicine, Weill Cornell Medical School, New York, NY 10065, USA.
Wayne
W
Tam
Department of Pathology, Mount Sinai Health System, New York, NY 10029, USA.
Julie
J
Teruya-Feldstein
Antitumor Assessment Core Facility and Molecular Pharmacology Department, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
Elisa
E
de Stanchina
Department of Pathology, City of Hope, Duarte, CA 91010, USA.
Wing C
WC
Chan
Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Sami N
SN
Malek
Centre for Lymphoid Cancer, British Columbia Cancer Agency and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
Daisuke
D
Ennishi
Department of Medicine, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
Renier J
RJ
Brentjens
Centre for Lymphoid Cancer, British Columbia Cancer Agency and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
Randy D
RD
Gascoyne
Centre National de la Recherche Scientifque, UMR 7276, Université de Limoges, 8700 Limoges, France.
Michel
M
Cogné
INSERM U917, Equipe labellisée Ligue contre le Cancer, Université Rennes 1, EFS Bretagne, CHU Rennes, 35000 Rennes, France. Electronic address: karin.tarte@univ-rennes1.fr.
Karin
K
Tarte
Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: wendelh@mskcc.org.
Hans-Guido
HG
Wendel
D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D006801:Humans; D008213:Lymphocyte Activation; D008224:Lymphoma, Follicular / Q000235:genetics / Q000628:therapy*; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy; D000072417:Protein Domains; D015202:Protein Engineering; D011971:Receptors, Immunologic / Q000378:metabolism*; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D059016:Tumor Microenvironment; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D018941:Antigens, CD19; C482586:BTLA protein, human; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins
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