Interferon signaling in ascites-associated macrophages is linked to a favorable clinical outcome in a subgroup of ovarian carcinoma patients.
Interferon signaling in ascites-associated macrophages is linked to a favorable clinical outcome in a subgroup of ovarian carcinoma patients.
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DOI：
10.1186/s12864-017-3630-9
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发表时间：
2017-03-21
期刊：
影响因子：
4.4
通讯作者：
Müller R
中科院分区：
文献类型：
--
作者：
Adhikary T;Wortmann A;Finkernagel F;Lieber S;Nist A;Stiewe T;Wagner U;Müller-Brüsselbach S;Reinartz S;Müller R
尽管肿瘤相关巨噬细胞（TAM）对癌症进展至关重要，但尚未报道不同临床结果与转录网络之间的联系。我们通过分析从卵巢癌患者腹水中分离的TAM的全球表达模式来解决这个问题。从不同卵巢癌患者中分离的TAM可以通过共表达或主成分分析分层为具有特定生物学特征并与不同临床结果相关的亚组。亚组A的标志是临床上不利的标志物的高表达，包括（i）高CD 163表达，抗炎活化状态的表面受体特征，（ii）增加的PCOLCE 2表达，指示增强的细胞外基质组织，和（iii）升高的IL-6和IL-10腹水水平，其与卵巢癌的侵袭性和免疫抑制有关。相反，亚组B TAM的特征在于与免疫防御机制和干扰素（IFN）信号传导相关的基因的上调。有趣的是，对1763名卵巢癌患者的已发表数据的分析显示，这种转录特征与较长的总生存期密切相关。与这些结果一致，IFNγ能够消除卵巢癌腹水对诱导IL-12 B表达和IL-12分泌的抑制作用，IL-12表达和IL-12分泌是细胞毒性免疫应答的关键决定因素。卵巢癌患者的生存与TAM的存在有关，TAM具有转录特征，其特征在于促肿瘤和免疫抑制标记物的低表达以及与干扰素信号传导相关的基因的上调。观察到的IFNγ介导的IL-12在腹水存在下的诱导恢复为干扰素信号相关特征与有利的临床结果的关联提供了可能的解释。本文的在线版本（doi：10.1186/s12864-017-3630-9）包含补充材料，可供授权用户使用。
Although tumor-associated macrophages (TAMs) are essential for cancer progression, connections between different clinical outcomes and transcriptional networks have not been reported. We have addressed this issue by analyzing global expression patterns of TAMs isolated from the ascites of ovarian cancer patients. TAMs isolated from different ovarian cancer patients can be stratified by coexpression or principal component analysis into subgroups with specific biological features and associated with distinct clinical outcomes. A hallmark of subgroup A is a high expression of clinically unfavorable markers, including (i) high CD163 expression, a surface receptor characteristic of an anti-inflammatory activation state, (ii) increased PCOLCE2 expression, indicative of enhanced extracellular matrix organization, and (iii) elevated ascites levels of IL-6 and IL-10, linked to the aggressiveness of ovarian cancer and immune suppression. In contrast, subgroup B TAMs are characterized by the upregulation of genes linked to immune defense mechanisms and interferon (IFN) signaling. Intriguingly, analysis of published data for 1763 ovarian cancer patients revealed a strong association of this transcriptional signature with a longer overall survival. Consistent with these results, IFNγ was able to abrogate the suppressive effect of ovarian cancer ascites on the inducibility of IL12B expression and IL-12 secretion, a key determinant of a cytotoxic immune response. The survival of ovarian cancer patients is linked to the presence of TAMs with a transcriptional signature that is characterized by a low expression of protumorigenic and immunosuppressive markers and an upregulation of genes linked to interferon signaling. The observed IFNγ-mediated restoration of the inducibility of IL-12 in the presence of ascites provides a possible explanation for the association of an interferon signaling-associated signature with a favorable clinical outcome. The online version of this article (doi:10.1186/s12864-017-3630-9) contains supplementary material, which is available to authorized users.