Department of Hematology, Oncology and Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Blood. 2011 Jul 28;118(4):1020-33. doi: 10.1182/blood-2010-11-321265. Epub 2011 May 17.
Lymphoma cell survival and progression are putatively dependent on a specific microanatomic localization within secondary lymphoid organs. Despite compelling data correlating homeostatic chemokine receptor expression and human lymphoma pathogenesis, genetic models that either mimic lymphoma dissemination or dissect a crosstalk of lymphoma and stromal cells are missing. Applying the genetically tractable Eμ-Myc transgenic mouse model, we show that the chemokine receptor CCR7 regulates Eμ-Myc lymphoma homing to lymph nodes and distinctive microanatomic sites of the spleen. CCR7-controlled access of lymphoma cells to the splenic T-cell zone led to a significant survival advantage compared with CCR7-deficient lymphoma cells, which were excluded from this zone. Within the niche, lymphoma cells stimulated a reciprocal cross-talk with gp38(+) fibroblastic reticular cells. This reciprocal cooperation program was mediated by lymphoma B cell-presented lymphotoxin, which acted on lymphotoxin-β-receptor-bearing stromal cells followed by alteration of stromal cellular composition. Cross-talk inhibition by lymphotoxin-α deletion and using a lymphotoxin-β receptor-immunoglobulin fusion protein impaired lymphoma growth. Thus, abrogation of CCR7-governed migration and of sustained lymphotoxin signaling could provide new targets in lymphoma therapy.
淋巴瘤细胞的存活和进展据称依赖于次级淋巴器官内的特定微观定位。尽管有大量数据表明稳态趋化因子受体表达与人类淋巴瘤发病机制相关，但缺乏模拟淋巴瘤传播或解析淋巴瘤与基质细胞串扰的遗传模型。应用遗传上可操作的 Eμ-Myc 转基因小鼠模型，我们表明趋化因子受体 CCR7 调节 Eμ-Myc 淋巴瘤向淋巴结和脾脏的特有微区的归巢。与 CCR7 缺陷的淋巴瘤细胞相比，CCR7 控制的淋巴瘤细胞进入脾脏 T 细胞区具有显著的生存优势，而 CCR7 缺陷的淋巴瘤细胞则被排斥出该区域。在龛位内，淋巴瘤细胞与 gp38(+)成纤维网状细胞刺激了一种互惠的串扰。这种互惠的合作程序由淋巴瘤 B 细胞呈递的淋巴毒素介导，作用于带有淋巴毒素-β 受体的基质细胞，随后改变基质细胞的组成。通过淋巴毒素-α 缺失和使用淋巴毒素-β 受体-免疫球蛋白融合蛋白进行的串扰抑制会损害淋巴瘤的生长。因此，阻断 CCR7 调控的迁移和持续的淋巴毒素信号传递可能为淋巴瘤治疗提供新的靶点。
