Lin28B-high breast cancer cells promote immune suppression in the lung pre-metastatic niche via exosomes and support cancer progression.
Lin28B-high breast cancer cells promote immune suppression in the lung pre-metastatic niche via exosomes and support cancer progression.
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Lin28B 高乳腺癌细胞通过外泌体促进肺转移前生态位的免疫抑制并支持癌症进展
DOI：
10.1038/s41467-022-28438-x
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发表时间：
2022-02-16
影响因子：
16.6
通讯作者：
Zhan L
中科院分区：
文献类型：
--
作者：
Qi M;Xia Y;Wu Y;Zhang Z;Wang X;Lu L;Dai C;Song Y;Xu K;Ji W;Zhan L
转移前小生境的形成是转移负荷的关键步骤。多能因子Lin 28 B经常在乳腺肿瘤中表达，并且在三阴性乳腺癌亚型中特别上调。在这里，我们证明了Lin 28 B通过建立免疫抑制的转移前小生境来促进乳腺癌的肺转移。Lin 28 B能够使中性粒细胞募集和N2转化。然后，N2嗜中性粒细胞通过PD-L2上调和失调的细胞因子环境对于转移前肺中的免疫抑制是必需的。我们还确定了具有低let-7的乳腺癌释放的外泌体是Lin 28 B诱导的免疫抑制的先决条件。此外，Lin 28 B诱导的乳腺癌干细胞是低let-7s外泌体的主要来源。临床数据进一步验证了肿瘤中高的Lin 28 B和低的let-7s都是乳腺癌患者预后不良和肺转移的指标。总之，这些数据揭示了Lin 28 B指导免疫抑制性转移前小生境形成的机制。转移前小生境的建立是转移形成之前的关键步骤。在这里，作者表明，肿瘤内在的Lin 28 B，一种RNA结合蛋白，在形成免疫抑制的转移前小生境中起着重要作用，促进乳腺癌的肺转移。
The formation of pre-metastatic niche is a key step in the metastatic burden. The pluripotent factor Lin28B is frequently expressed in breast tumors and is particularly upregulated in the triple negative breast cancer subtype. Here, we demonstrate that Lin28B promotes lung metastasis of breast cancer by building an immune-suppressive pre-metastatic niche. Lin28B enables neutrophil recruitment and N2 conversion. The N2 neutrophils are then essential for immune suppression in pre-metastatic lung by PD-L2 up-regulation and a dysregulated cytokine milieu. We also identify that breast cancer-released exosomes with low let-7s are a prerequisite for Lin28B-induced immune suppression. Moreover, Lin28B-induced breast cancer stem cells are the main sources of low-let-7s exosomes. Clinical data further verify that high Lin28B and low let-7s in tumors are both indicators for poor prognosis and lung metastasis in breast cancer patients. Together, these data reveal a mechanism by which Lin28B directs the formation of an immune-suppressive pre-metastatic niche. The establishment of a pre-metastatic niche is a key step preceding metastasis formation. Here the authors show that tumor-intrinsic Lin28B, a RNA-binding protein, has an essential role in the formation of an immune-suppressive pre-metastatic niche, promoting lung metastasis of breast cancer.
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