CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10 | Zendy

Ian H. Guldner | Zendy; Qingfei Wang | Zendy; Lin Yang | Zendy; Samantha M. Golomb | Zendy; Zhuo Zhao | Zendy; Jacqueline Lopez | Zendy; Abigail Brunory | Zendy; Erin N. Howe | Zendy; Yizhe Zhang | Zendy; Bhavana Palakurthi | Zendy; Martin Barron | Zendy; Hongyu Gao | Zendy; Xiaoling Xuei | Zendy; Yunlong Liu | Zendy; Jun Li | Zendy; Danny Z. Chen | Zendy; Gary E. Landreth | Zendy; Siyuan Zhang | Zendy

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CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10

Author(s) -

Ian H. Guldner,

Qingfei Wang,

Lin Yang,

Samantha M. Golomb,

Zhuo Zhao,

Jacqueline Lopez,

Abigail Brunory,

Erin N. Howe,

Yizhe Zhang,

Bhavana Palakurthi,

Martin Barron,

Hongyu Gao,

Xiaoling Xuei,

Yunlong Liu,

Jun Li,

Danny Z. Chen,

Gary E. Landreth,

Siyuan Zhang

Publication year - 2020

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2020.09.064

Subject(s) - biology , myeloid , immune system , immunology , cxcl10 , cancer research , myeloid leukemia , downregulation and upregulation , chemokine , gene , biochemistry

Brain metastasis (br-met) develops in an immunologically unique br-met niche. Central nervous system-native myeloid cells (CNS-myeloids) and bone-marrow-derived myeloid cells (BMDMs) cooperatively regulate brain immunity. The phenotypic heterogeneity and specific roles of these myeloid subsets in shaping the br-met niche to regulate br-met outgrowth have not been fully revealed. Applying multimodal single-cell analyses, we elucidated a heterogeneous but spatially defined CNS-myeloid response during br-met outgrowth. We found Ccr2 + BMDMs minimally influenced br-met while CNS-myeloid promoted br-met outgrowth. Additionally, br-met-associated CNS-myeloid exhibited downregulation of Cx3cr1. Cx3cr1 knockout in CNS-myeloid increased br-met incidence, leading to an enriched interferon response signature and Cxcl10 upregulation. Significantly, neutralization of Cxcl10 reduced br-met, while rCxcl10 increased br-met and recruited VISTA Hi PD-L1 + CNS-myeloid to br-met lesions. Inhibiting VISTA- and PD-L1-signaling relieved immune suppression and reduced br-met burden. Our results demonstrate that loss of Cx3cr1 in CNS-myeloid triggers a Cxcl10-mediated vicious cycle, cultivating a br-met-promoting, immune-suppressive niche.

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