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

Ian H Guldner; Qingfei Wang; Lin Yang; Samantha M Golomb; Zhuo Zhao; Jacqueline A 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

doi:10.1016/j.cell.2020.09.064

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

Cell. 2020 Nov 25;183(5):1234-1248.e25. doi: 10.1016/j.cell.2020.09.064. Epub 2020 Oct 27.

Authors

Ian H Guldner¹, Qingfei Wang¹, Lin Yang², Samantha M Golomb¹, Zhuo Zhao², Jacqueline A Lopez³, Abigail Brunory¹, Erin N Howe¹, Yizhe Zhang², Bhavana Palakurthi¹, Martin Barron⁴, Hongyu Gao⁵, Xiaoling Xuei⁵, Yunlong Liu⁵, Jun Li⁴, Danny Z Chen², Gary E Landreth⁶, Siyuan Zhang⁷

Affiliations

¹ Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA; Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA.
² Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; Department of Computer Science and Engineering, College of Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
³ Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA.
⁴ Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN 46556, USA.
⁵ Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA.
⁶ Indiana University School of Medicine Stark Neuroscience Research Institute, Indianapolis, IN 46202, USA.
⁷ Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA; Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA. Electronic address: szhang8@nd.edu.

Abstract

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.

Keywords: Brain metastasis; T cells; bone marrow-derived myeloid cells; brain immunity; cancer immunology; immune suppression; immune therapy; metastatic niche; microglia; tumor microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Bone Marrow Cells / metabolism
Brain Neoplasms / genetics
Brain Neoplasms / immunology*
Brain Neoplasms / pathology
Brain Neoplasms / secondary*
CX3C Chemokine Receptor 1 / metabolism
Central Nervous System / pathology
Chemokine CXCL10 / metabolism*
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Immunosuppression Therapy*
Interferons / metabolism
Macrophages / metabolism
Membrane Proteins / metabolism
Mice, Inbred C57BL
Mice, Knockout
Myeloid Cells / metabolism*
Neutralization Tests
Phenotype
T-Lymphocytes / immunology
Transcriptome / genetics

Substances

CX3C Chemokine Receptor 1
Chemokine CXCL10
Cx3cr1 protein, mouse
Membrane Proteins
Vsir protein, mouse
Interferons

Abstract

Publication types

MeSH terms

Substances

Grants and funding