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.

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Key Points IgM+ FL B cells display a stronger BCR response than their GC B-cell counterpart despite significant BCR-related phosphatase activity. M2 macrophages trigger DC-SIGN–dependent cell adhesion and BCR activation in IgM+ FL B cells with a highly mannosylated BCR.