Lin28B-high breast cancer cells promote immune suppression in the lung pre-metastatic niche via exosomes and support cancer progression

Meiyan Qi,Weiwei Ji,Lixing Zhan,Zhuo Zhang,Yanjun Wu,Yun Xia,Yanan Song,Keying Xu,Liying Lu,Xinyu Wang,Cheng Dai

doi:10.1038/s41467-022-28438-x

Abstract

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.

Highlights

The formation of pre-metastatic niche is a key step in the metastatic burden
We found that Lin28B was significantly higher in triple-negative breast cancer (TNBC) relative to the luminal or HER2+ subtypes (Fig. 1d)
To test whether N2 neutrophils are directly involved in CD4+ and CD8+ T cell activation, we activated spleen naïve CD4+ and CD8+ T cells in vitro using anti-CD3/CD28 antibodies alone or in the context of co-culture with pre-metastatic lung-derived neutrophils, and the results showed that N2 neutrophils markedly reduced CD44+CD62L− populations in both CD4+ and CD8+ T cells (Fig. 4f)

Summary

Introduction

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 upregulated in the triple negative breast cancer subtype. We demonstrate that Lin28B promotes lung metastasis of breast cancer by building an immune-suppressive pre-metastatic niche. 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. We determine that Lin28B can establish an immunosuppressive pre-metastatic niche by inducing neutrophil infiltration and N2 conversion, which depends on the tumor-released exosomes with low let-7s. We show that Lin28B induces primary tumors to produce more ALDH+ breast cancer stem cells (BCSCs), the principal source for tumor exosomes with low let-7s. Our study exposes a mechanism by which Lin28B dictates breast cancer metastasis through shaping immunosuppression in the metastatic lung niche

Methods

Results

Conclusion