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

Cell | 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 (T) 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) 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

Antibodies used in this publication

Associated grants

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

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dbNSFP (tool)

RRID:SCR_005178

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