Lymphoma: Customized therapeutic delivery

Abstract

HVEM (also known as TNFRSF14) are frequent in B cell lymphomas, but how these mutations contribute to lymphoma biology is not known. Boice, Salloum, Mourcin et al. have shown that HVEM is an important tumour suppressor in lymphomas and that direct delivery of a soluble HVEM peptide using engineered T cells might be therapeutically beneficial. The authors first examined genomic data for a collection of human follicular lymphomas (FLs) and confirmed that mutation or loss of the HVEM locus was common. HVEM protein expression was also lost in approximately one-third of FLs. Furthermore, Band T-lymphocyte attenuator (BTLA), the only known HVEM-binding partner expressed by B cells, was also lost in many FLs, and losses of BTLA and HVEM occurred in a mutually exclusive manner. In a mouse model that recapitulates key aspects of BCL-2-expressing human FL (VavP‐Bcl2 mice), knockdown of Hvem accelerated lymphoma genesis. Several important signalling molecules were also activated in these lymphomas, including many related to the B cell receptor (BCR) pathway. Similar results were observed with Btla knockdown in this model. A purified soluble HVEM ectodomain fragment (solHVEM) inhibited BCR signalling in isolated lymphoma cells from these mice or from patients with FL to a similar extent as a BCR pathway inhibitor (the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib), and this inhibition depended on the presence of BTLA. In addition to this lymphoma cell-autonomous effect of HVEM, HVEM loss also affected the lymphoma microenvironment. The authors found that HVEMdeficient lymphoma cells had increased production of stromaactivating tumour necrosis factor (TNF) family cytokines, which was reduced by treatment with solHVEM. Furthermore, Hvem-knockdown lymphomas in mice had increased numbers of infiltrating follicular dendritic cells (FDCs) and increased fibroblastic reticular cell (FRC) activation, as well as increased levels of FDCand FRC-derived cytokines. One of these cytokines, C-X-C motif chemokine 13 (CXCL13), functions to recruit T follicular helper (TFH) cells, and indeed TFH cell numbers — and in turn the cytokines they produce — were increased in Hvem-knockdown lymphomas. Could solHVEM be used therapeutically? SolHVEM inhibited in vitro growth of lymphoma cell lines that expressed high levels of BTLA, but not of those that expressed low BTLA as those cells typically had high HVEM expression. Similar results were observed in vivo: intratumoural injection of solHVEM inhibited the growth of established lymphomas that lacked HVEM and expressed BTLA. However, systemic solHVEM delivery had only a modest effect. To deliver solHVEM locally, the authors then engineered CD19-chimeric antigen receptor (CAR) T cells (which target B cells) to produce solHVEM. Although CD19-CAR T cells alone had a therapeutic benefit against xenografted human FL cells (DoHH2 cells), treatment with cells that also produced solHVEM had a greater effect. These data highlight the importance of HVEM–BTLA signalling in FL in both lymphoma cells and the microenvironment, as well as the possibility of using engineered CAR T cells to produce proteins with therapeutic potential. Sarah Seton‐Rogers LY M P H O M A

DOI: 10.1038/nrc.2016.121

Cite this paper

@article{SetonRogers2016LymphomaCT, title={Lymphoma: Customized therapeutic delivery}, author={Sarah E Seton-Rogers}, journal={Nature Reviews Cancer}, year={2016}, volume={16}, pages={756-757} }