Type I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment

Weili Ma, Maria Cecília Oliveira-Nunes, Ke Xu, Andrew Kossenkov, Benjamin C. Reiner, Richard C. Crist, James Hayden and Qing Chen ()
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Weili Ma: The Wistar Institute
Maria Cecília Oliveira-Nunes: The Wistar Institute
Ke Xu: Boston University School of Medicine
Andrew Kossenkov: The Wistar Institute
Benjamin C. Reiner: The University of Pennsylvania
Richard C. Crist: The University of Pennsylvania
James Hayden: The Wistar Institute
Qing Chen: The Wistar Institute

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Cancer metastasis to the brain is a significant clinical problem. Metastasis is the consequence of favorable interactions between invaded cancer cells and the microenvironment. Here, we demonstrate that cancer-activated astrocytes create a sustained low-level activated type I interferon (IFN) microenvironment in brain metastatic lesions. We further confirm that the IFN response in astrocytes facilitates brain metastasis. Mechanistically, IFN signaling in astrocytes activates C-C Motif Chemokine Ligand 2 (CCL2) production, which further increases the recruitment of monocytic myeloid cells. The correlation between CCL2 and monocytic myeloid cells is confirmed in clinical brain metastasis samples. Lastly, genetically or pharmacologically inhibiting C-C Motif Chemokine Receptor 2 (CCR2) reduces brain metastases. Our study clarifies a pro-metastatic effect of type I IFN in the brain even though IFN response has been considered to have anti-tumor effects. Moreover, this work expands our understandings on the interactions between cancer-activated astrocytes and immune cells in brain metastasis.

Date: 2023
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DOI: 10.1038/s41467-023-38252-8

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