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

Cell | Oct 6, 2016

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.

Pubmed ID: 27693350 RIS Download

Mesh terms: Adoptive Transfer | Animals | Antigens, CD19 | B-Lymphocytes | Cell Proliferation | Humans | Lymphocyte Activation | Lymphoma, Follicular | Mice | Neoplasms, Experimental | Protein Domains | Protein Engineering | Receptors, Immunologic | Receptors, Tumor Necrosis Factor, Member 14 | Recombinant Fusion Proteins | T-Lymphocytes | Tumor Microenvironment | Tumor Suppressor Proteins | Xenograft Model Antitumor Assays

Research resources used in this publication

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA190384
  • Agency: NCI NIH HHS, Id: R01 CA138738
  • Agency: NCI NIH HHS, Id: R01 CA183876
  • Agency: NCI NIH HHS, Id: P50 CA192937
  • Agency: NCRR NIH HHS, Id: P41 RR000862
  • Agency: NCI NIH HHS, Id: P30 CA008748
  • Agency: NCI NIH HHS, Id: P01 CA190174
  • Agency: NCI NIH HHS, Id: P01 CA059350
  • Agency: NCI NIH HHS, Id: R01 CA142798
  • Agency: NCI NIH HHS, Id: R01 CA207217
  • Agency: , Id: P50 CA192937

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SnpEff

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ImageJ

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Primer3

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dbNSFP

A database for functional prediction and annotation of all potential non-synonymous single-nucleotide variants (nsSNVs) in the human genome. Version 2.0 is based on the Gencode release 9 / Ensembl version 64 and includes a total of 87,347,043 nsSNVs and 2,270,742 essential splice site SNVs. It compiles prediction scores from six prediction algorithms (SIFT, Polyphen2, LRT, MutationTaster, MutationAssessor and FATHMM), three conservation scores (PhyloP, GERP++ and SiPhy) and other related information including allele frequencies observed in the 1000 Genomes Project phase 1 data and the NHLBI Exome Sequencing Project, various gene IDs from different databases, functional descriptions of genes, gene expression and gene interaction information, etc. Some dbNSFP contents (may not be up-to-date though) can also be accessed through variant tools, ANNOVAR, KGGSeq, UCSC Genome Browser''s Variant Annotation Integrator, Ensembl Variant Effect Predictor and HGMD.

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IMGT - the international ImMunoGeneTics information system

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