Tumor-induced stromal reprogramming drives lymph node transformation.
Tumor-induced stromal reprogramming drives lymph node transformation.
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DOI：
10.1038/ni.3492
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发表时间：
2016-09
影响因子：
30.5
通讯作者：
Shields J
中科院分区：
文献类型：
--
作者：
Riedel A;Shorthouse D;Haas L;Hall BA;Shields J
淋巴结（LN）基质细胞，特别是成纤维网状细胞（FRC），提供关键的结构支持和调节免疫，耐受和运输特性的LN。在许多肿瘤中，LN转移预示着预后不良。然而，基质的贡献，不断发展的微环境的肿瘤引流淋巴结（TDLNs）仍然知之甚少。在这里，我们表明，FRCs特别是TDLNs增殖，以响应肿瘤来源的线索，他们形成的网络被重塑。非引流和TDLN FRC的比较转录分析证明了关键途径的重编程，包括基质重塑、趋化因子/细胞因子信号传导和免疫功能，包括白细胞募集、迁移和活化。特别是，FRC衍生的CCL 21和IL-7的下调伴随着免疫组成的改变和异常定位。这些数据表明，TDLN的基质在暴露于肿瘤衍生因子后在多个水平上适应，以表现出通常与免疫抑制相关的特征。
Lymph node (LN) stromal cells, particularly fibroblastic reticular cells (FRCs), provide critical structural support and regulate immunity, tolerance and transport properties of LNs. In many tumors, LN metastasis is predictive of poor prognosis. However, the stromal contribution to the evolving microenvironment of tumor draining LNs (TDLNs) remains poorly understood. Here we show that FRCs specifically of TDLNs proliferate in response to tumor-derived cues and that the network they form is remodeled. Comparative transcriptional analysis of non-draining and TDLN FRCs demonstrated reprogramming of key pathways including matrix remodeling, chemokine/cytokine signaling and immune functions including leukocyte recruitment, migration and activation. In particular, downregulation of FRC-derived CCL21 and IL-7 were accompanied by altered immune composition and aberrant localization. These data imply that stroma of TDLNs adapt on multiple levels, following exposure to tumor-derived factors, to exhibit features typically associated with immune suppression.