Midkine activation of CD8+ T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth
Open Access
- 1 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-15
- https://doi.org/10.1038/s41467-020-15770-3
Abstract
Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1-mutant human and mouse brain neurons elaborate midkine to activate naive CD8(+) T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting. The role of neurons and T cells in glioma progression remains poorly understood. Here the authors show that midkine-dependent activation of a neuron-T cell-microglia axis promotes the growth of optic pathway gliomas.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (1-R35-NS07211-01)
This publication has 69 references indexed in Scilit:
- MPA Modulates Tight Junctions' Permeability via Midkine/PI3K Pathway in Caco-2 Cells: A Possible Mechanism of Leak-Flux Diarrhea in Organ Transplanted PatientsFrontiers in Physiology, 2017
- Characterization of Distinct Immunophenotypes across Pediatric Brain Tumor TypesThe Journal of Immunology, 2013
- Autonomic Nerve Development Contributes to Prostate Cancer ProgressionScience, 2013
- Regulation of learning and memory by meningeal immunity: a key role for IL-4The Journal of Experimental Medicine, 2010
- Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson diseaseJCI Insight, 2008
- Detail Histologic Analysis of Nerve Plexus Invasion in Invasive Ductal Carcinoma of the Pancreas and Its Prognostic ImpactThe American Journal of Surgical Pathology, 2007
- Circulating Growth Factor Levels Are Associated with Tumorigenesis in Neurofibromatosis Type 1Clinical Cancer Research, 2004
- Neuronal adhesion molecule telencephalin induces rapid cell spreading of microgliaBrain Research, 1999
- Functional GABAA receptors on human glioma cellsEuropean Journal of Neuroscience, 1998
- Prevention of experimental autoimmune encephalomyelitis by antibodies against α4βl integrinNature, 1992