Boice Michael, Salloum Darin, Mourcin Frederic, Sanghvi Viraj, Amin Rada, Oricchio Elisa, Jiang Man, Mottok Anja, Denis-Lagache Nicolas, Ciriello Giovanni, Tam Wayne, Teruya-Feldstein Julie, de Stanchina Elisa, Chan Wing C, Malek Sami N, Ennishi Daisuke, Brentjens Renier J, Gascoyne Randy D, Cogné Michel, Tarte Karin, Wendel Hans-Guido
Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Cell. 2016 Oct 6;167(2):405-418.e13. doi: 10.1016/j.cell.2016.08.032. Epub 2016 Sep 29.
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) 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) 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.
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。我们报告称，HVEM的缺失导致B细胞增殖的细胞自主激活，并在体内驱动GC淋巴瘤的发展。缺乏HVEM的淋巴瘤B细胞还会诱导一种肿瘤支持性微环境，其特征是淋巴样基质激活加剧和T滤泡辅助（T）细胞募集增加。这些变化是由于HVEM和BTLA（B和T淋巴细胞衰减器）受体之间抑制性细胞间相互作用的破坏所致。因此，给予HVEM胞外域蛋白（solHVEM）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，我们构建了靶向CD19的嵌合抗原受体（CAR）T细胞，其可在局部持续产生solHVEM。这些经过修饰的CAR-T细胞对异种移植淋巴瘤显示出增强的治疗活性。因此，HVEM-BTLA轴对抗淋巴瘤的发展，我们的研究说明了使用CAR-T细胞作为能够递送抗癌蛋白的“微型药房”。
