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Spatial and temporal mapping of breast cancer lung metastases identify TREM2 macrophages at the metastatic boundary

ABSTRACT: Cancer mortality is primarily caused by metastatic recurrence, whereby tumor cells evade immune surveillance. Better understanding of the molecular and cellular events that occur in metastatic niches is essential to develop effective immunotherapies targeting metastasis. We employed a model of spontaneous breast cancer lung metastasis to create a single-cell RNA-sequencing temporal and spatial atlas that spans different metastatic stages and regions. We found that pre-metastatic lungs are infiltrated by inflammatory neutrophils and monocytes, followed by accumulation of suppressive macrophages with the emergence of metastases. Metastasis-associated immune cells are present in the metastasis core, with the exception of Trem2+ regulatory macrophages uniquely enriched in the metastatic invasive margin. These regulatory macrophages contribute to the formation of an immune-suppressive niche, cloaking the tumor cells from immune surveillance. Our study provides a comprehensive chart of immune cell dynamics across metastatic stages and niches, which could inform the development of immunotherapies that target metastasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE231915 | GEO | 2023/10/02

REPOSITORIES: GEO

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Project description:Cervical cancer (CC) is one of the most common malignancy in women worldwide. It is characterized by a natural continuous phenomenon, that is, it is in the initial stage of HPV infection, progresses to intraepithelial neoplasia, and then develops into invasion and metastasis. Determining the complexity of tumor microenvironment (TME) can deepen our understanding of lesion progression and provide novel therapeutic strategies for CC. We performed the single-cell RNA sequencing on the normal cervix, intraepithelial neoplasia, primary tumor and metastatic lymph node tissues to describe the composition, lineage, and functional status of immune cells and mesenchymal cells at different stages of CC progression. A total of 59913 single cells were obtained and divided into 9 cellular clusters, including immune cells (T/NK cells, macrophages, B cells, plasma cells, mast cells and neutrophils) and mesenchymal cells (endothelial cells, smooth muscle cells and fibroblasts). Our results showed that there were distinct cell subpopulations in different stages of CC. High-stage intraepithelial neoplasia (HSIL) tissue exhibited a low, recently activated TME, and it was characterized by high infiltration of tissue-resident CD8 T cell, effector NK cells, Treg, DC1, pDC, and M1-like macrophages. Tumor tissue displayed high enrichment of exhausted CD8 T cells, resident NK cells and M2-like macrophages, suggesting immunosuppressive TME. Metastatic lymph node consisted of naive T cell, central memory T cell, circling NK cells, cytotoxic CD8+ T cells and effector memory CD8 T cells, suggesting an early activated phase of immune response. This study is the first to delineate the transcriptome profile of immune cells during CC progression using single-cell RNA sequencing. Our results indicated that HSIL exhibited a low, recently activated TME, tumor displayed immunosuppressive statue, and metastatic lymph node showed early activated phase of immune response. Our study enhanced the understanding of dynamic change of TME during CC progression and has implications for the development of novel treatments to inhibit the initiation and progression of CC.

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Spatial and temporal mapping of breast cancer lung metastases identify TREM2 macrophages at the metastatic boundary

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