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Cell. 2016 Oct 6;167(2):405-418.e13. doi: 10.1016/j.cell.2016.08.032. Epub 2016 Sep 29.

Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.

Author information

1
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.
2
Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
3
INSERM U917, Equipe labellisée Ligue contre le Cancer, Université Rennes 1, EFS Bretagne, CHU Rennes, 35000 Rennes, France.
4
Swiss Institute for Cancer Research (ISREC), EPFL SV-Batiment 19, 1003 Lausanne, Switzerland.
5
Centre for Lymphoid Cancer, British Columbia Cancer Agency and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
6
Centre National de la Recherche Scientifque, UMR 7276, Université de Limoges, 8700 Limoges, France.
7
Department of Computational Biology, University of Lausanne, Rue du Bugnon 27, 1005 Lausanne, Switzerland; The Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
8
Department of Pathology and Laboratory Medicine, Weill Cornell Medical School, New York, NY 10065, USA.
9
Department of Pathology, Mount Sinai Health System, New York, NY 10029, USA.
10
Antitumor Assessment Core Facility and Molecular Pharmacology Department, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
11
Department of Pathology, City of Hope, Duarte, CA 91010, USA.
12
Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
13
Department of Medicine, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
14
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.
15
Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: wendelh@mskcc.org.

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.

PMID:
27693350
PMCID:
PMC5221752
DOI:
10.1016/j.cell.2016.08.032
[Indexed for MEDLINE]
Free PMC Article

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