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

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.

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…Furthermore, it is feasible to engineer T cells to secrete checkpoint blockers [259][260][261] (Fig. 1) or HVEM [262] to lower the immunosuppressive pressure in the tumor vicinity.…”

IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma

“…Immunohistochemistry for pSTAT6 and CXCL12 was applied to a tissue microarray of 195 formalin-fixed paraffin-embedded tissue specimens from 186 patients diagnosed with FL. 27,28 For details, see the supplemental Data (available on the Blood Web site).…”

Programming CAR-T cells to kill cancer

“…An alternative approach for cancer immunotherapy is based on the use of T cells as vehicles to deliver therapeutic agents to the tumour site. T cells engineered to secrete a soluble form of herpes virus entry mediator that inhibited B-cell lymphoma proliferation through the B and T lymphocyte attenuator signalling axis augmented the efficacy of CD19-CAR-T therapy 184 . A separate study reported a versatile system, termed 'synNotch' , for the integration of signals from molecular stimuli in the local microenvironment into cellular responses 185 .…”