Loss of the HVEM tumor suppressor in lymphoma and restoration by modified CAR-T cells

• Michael Boice ^[1] ; Darin Salloum ^[1] ; Frederic Mourcin ^[2]
  1. [1] Memorial Sloan Kettering Cancer Center

     Memorial Sloan Kettering Cancer Center

     Estados Unidos

     
  2. [2] Université Rennes
• Localización: Cell, ISSN 0092-8674, Vol. 167, Nº. 2, 2016, págs. 405-418
• Idioma: inglés
• Texto completo no disponible (Saber más ...)
• Resumen

  • 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.