TY - JOUR
T1 - Type I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment
AU - Ma, Weili
AU - Oliveira-Nunes, Maria Cecília
AU - Xu, Ke
AU - Kossenkov, Andrew
AU - Reiner, Benjamin C
AU - Crist, Richard C
AU - Hayden, James
AU - Chen, Qing
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/5/6
Y1 - 2023/5/6
N2 - 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.
AB - 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.
KW - Humans
KW - Interferon Type I/metabolism
KW - Astrocytes/metabolism
KW - Chemokine CCL2/metabolism
KW - Myeloid Cells/metabolism
KW - Brain Neoplasms/pathology
KW - Receptors, CCR2/metabolism
KW - Tumor Microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85157975828&partnerID=8YFLogxK
M3 - Article
C2 - 37149684
SN - 2041-1723
VL - 14
SP - 2632
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2632
ER -