Midkine activation of CD8+ T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth.

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 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.

• Authors: Xiaofan Guo, Yuan Pan, Min Xiong, Shilpa Sanapala, Corina Anastasaki, Olivia Cobb, Sonika Dahiya, David H Gutmann
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 2177 (05 01 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32358581 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CCL4
• Chemokine CCL5
• Low Density Lipoprotein Receptor-Related Protein-1
• Lrp1 protein, mouse
• Midkine

Topics

• Animals
• Apoptosis (immunology)
• Astrocytoma (immunology, mortality, pathology)
• Brain Neoplasms (immunology, mortality, pathology)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cell Proliferation
• Chemokine CCL4 (metabolism)
• Chemokine CCL5 (metabolism)
• Child
• Female
• Humans
• Induced Pluripotent Stem Cells
• Low Density Lipoprotein Receptor-Related Protein-1 (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microglia (immunology, metabolism)
• Midkine (metabolism)
• Neurofibromatosis 1 (genetics, metabolism)
• Neurons (metabolism)
• Optic Nerve Glioma (immunology, mortality, pathology)
• Tumor Microenvironment (immunology)