Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 27693350.
- Also identified by DOI 10.1016/j.cell.2016.08.032 and PMC identifier 5221752.
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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 (T<sub>FH</sub>) 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<sup>(P37-V202)</sup>) 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.
Medical subject headings
- Adoptive Transfer
- Lymphoma, Follicular
- Receptors, Immunologic
- Receptors, Tumor Necrosis Factor, Member 14
- T-Lymphocytes
- Tumor Suppressor Proteins