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

Xiaofan Guo, Yuan Pan, Min Xiong, Shilpa Sanapala, Corina Anastasaki, Olivia Cobb, Sonika Dahiya and David H. Gutmann ()
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Xiaofan Guo: Washington University School of Medicine
Yuan Pan: Washington University School of Medicine
Min Xiong: Washington University School of Medicine
Shilpa Sanapala: Washington University School of Medicine
Corina Anastasaki: Washington University School of Medicine
Olivia Cobb: Washington University School of Medicine
Sonika Dahiya: Washington University School of Medicine
David H. Gutmann: Washington University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15770-3

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