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Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth
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Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth
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Journal Article
Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth
2020
Overview
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 naïve 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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/100
/ 13/106
/ 13/2
/ 13/31
/ 13/44
/ 13/51
/ 14/34
/ 38/77
/ 82/1
/ 82/51
/ 82/80
/ Animals
/ Brain
/ Brain Neoplasms - immunology
/ CD8-Positive T-Lymphocytes - immunology
/ CD8-Positive T-Lymphocytes - metabolism
/ Child
/ Female
/ Glioma
/ Humanities and Social Sciences
/ Humans
/ Induced Pluripotent Stem Cells
/ Low Density Lipoprotein Receptor-Related Protein-1 - metabolism
/ Male
/ Mice
/ Midkine
/ Neurofibromatosis 1 - genetics
/ Neurofibromatosis 1 - metabolism
/ Neurons
/ Optic Nerve Glioma - immunology
/ Optic Nerve Glioma - mortality
/ Optic Nerve Glioma - pathology
/ Science
/ Survival
/ Tumor Microenvironment - immunology
/ Tumors
