Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells Academic Article uri icon

Overview

MeSH Major

  • Adoptive Transfer
  • Lymphoma, Follicular
  • Receptors, Immunologic
  • Receptors, Tumor Necrosis Factor, Member 14
  • T-Lymphocytes
  • Tumor Suppressor Proteins

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.

publication date

  • October 6, 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5221752

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2016.08.032

PubMed ID

  • 27693350

Additional Document Info

start page

  • 405

end page

  • 418.e13

volume

  • 167

number

  • 2