Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.
Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.
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淋巴瘤中HVEM肿瘤抑制剂的丧失和修饰的CAR-T细胞恢复。
DOI：
10.1016/j.cell.2016.08.032
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发表时间：
2016-10-06
期刊：
影响因子：
64.5
通讯作者：
Wendel HG
中科院分区：
文献类型：
--
作者：
Boice M;Salloum D;Mourcin F;Sanghvi V;Amin R;Oricchio E;Jiang M;Mottok A;Denis-Lagache N;Ciriello G;Tam W;Teruya-Feldstein J;de Stanchina E;Chan WC;Malek SN;Ennishi D;Brentjens RJ;Gascoyne RD;Cogné M;Tarte K;Wendel HG
HVEM（TNFRSF14）受体基因是生发中心淋巴瘤中最常发生突变的基因之一。我们报道，HVEM的缺失导致B细胞增殖的细胞自主性激活，并在体内驱动生发中心淋巴瘤的发生。HVEM缺陷型淋巴瘤B细胞还诱导形成一种肿瘤支持性微环境，其特征是淋巴间质激活加剧以及T滤泡辅助细胞（TFH）募集增加。这些变化是由于HVEM和BTLA（B和T淋巴细胞衰减因子）受体之间抑制性细胞 - 细胞相互作用被破坏所致。因此，给予HVEM胞外域蛋白（solHVEM(P37 - V202)）可结合BTLA并恢复肿瘤抑制作用。为了在体内将solHVEM递送至淋巴瘤，我们设计了靶向CD19的嵌合抗原受体（CAR）T细胞，使其能够局部且持续地产生solHVEM。这些经过改造的CAR - T细胞对异种移植的淋巴瘤显示出增强的治疗活性。因此，HVEM - BTLA轴对抗淋巴瘤的发生，并且我们的研究阐明了CAR - T细胞作为能够递送抗癌蛋白的“微型药房”的用途。
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.