The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome.
The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome.
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肺肿瘤浸润性树突状细胞的转录组揭示出一种支持肿瘤的表型，以及一组对临床结局有负面影响的微小RNA特征。
DOI：
10.1080/2162402x.2016.1253655
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发表时间：
2017
期刊：
影响因子：
7.2
通讯作者：
Vermaelen KY
中科院分区：
文献类型：
--
作者：
Pyfferoen L;Brabants E;Everaert C;De Cabooter N;Heyns K;Deswarte K;Vanheerswynghels M;De Prijck S;Waegemans G;Dullaers M;Hammad H;De Wever O;Mestdagh P;Vandesompele J;Lambrecht BN;Vermaelen KY
靶向免疫调节通路开创了肺癌治疗的新时代。进一步的进展需要更深入地了解肺癌微环境中免疫细胞的生物学。树突状细胞（Dendritic cells，DC）是一种异质性的、可塑性很强的免疫细胞系统，在免疫应答的调控中起着重要作用。肿瘤内浸润和DC的活化状态正在成为肺癌的临床相关参数。在这项研究中，我们使用了原位肺癌临床前模型来剖析肺肿瘤微环境如何影响组织驻留DC，并提取新的生物学和临床相关信息。发现表达通用DC标志物的肺肿瘤浸润性白细胞主要由CD 11b+细胞组成，与瘤周肺DC对应物相比，CD 11b+细胞强烈过表达T细胞抑制分子PD-L1并获得肿瘤相关巨噬细胞（TAM）的经典表面标志物。这些CD 11b+肿瘤浸润DC（TIDCs）的转录组分析表明抗肿瘤免疫原性受损，证实了向TAM相关特征的倾斜，并表明暴露于缺氧环境。同时，TIDCs显示出由原型肺癌oncomir miR-31主导的特异性microRNA（miRNA）特征。在体外，缺氧驱动CD 11b + DC中的固有miR-31表达。过表达miR-31的CD 11b + DC的条件培养基诱导促侵袭性肺癌细胞形状变化并富含促转移可溶性因子最后，TCGA数据集的分析揭示了TIDC相关的miRNA特征在非小细胞肺癌中具有负面的预后影响。总之，这些数据表明了一种新的机制，通过这种机制，肺癌微环境利用DC系统的可塑性来支持肿瘤进展。
Targeting immunomodulatory pathways has ushered a new era in lung cancer therapy. Further progress requires deeper insights into the biology of immune cells in the lung cancer micro-environment. Dendritic cells (DCs) represent a heterogeneous and highly plastic immune cell system with a central role in controlling immune responses. The intratumoral infiltration and activation status of DCs are emerging as clinically relevant parameters in lung cancer. In this study, we used an orthotopic preclinical model of lung cancer to dissect how the lung tumor micro-environment affects tissue-resident DCs and extract novel biologically and clinically relevant information. Lung tumor-infiltrating leukocytes expressing generic DC markers were found to predominantly consist of CD11b+ cells that, compare with peritumoral lung DC counterparts, strongly overexpress the T-cell inhibitory molecule PD-L1 and acquire classical surface markers of tumor-associated macrophages (TAMs). Transcriptome analysis of these CD11b+ tumor-infiltrating DCs (TIDCs) indicates impaired antitumoral immunogenicity, confirms the skewing toward TAM-related features, and indicates exposure to a hypoxic environment. In parallel, TIDCs display a specific microRNA (miRNA) signature dominated by the prototypical lung cancer oncomir miR-31. In vitro, hypoxia drives intrinsic miR-31 expression in CD11b+ DCs. Conditioned medium of miR-31 overexpressing CD11b+ DCs induces pro-invasive lung cancer cell shape changes and is enriched with pro-metastatic soluble factors. Finally, analysis of TCGA datasets reveals that the TIDC-associated miRNA signature has a negative prognostic impact in non-small cell lung cancer. Together, these data suggest a novel mechanism through which the lung cancer micro-environment exploits the plasticity of the DC system to support tumoral progression.