TY - JOUR
T1 - Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth
AU - Guo, Xiaofan
AU - Pan, Yuan
AU - Xiong, Min
AU - Sanapala, Shilpa
AU - Anastasaki, Corina
AU - Cobb, Olivia
AU - Dahiya, Sonika
AU - Gutmann, David H.
N1 - Funding Information:
This work was partially funded by a grant from National Institute of Neurological Disorders and Stroke (1-R35-NS07211-01) to D.H.G., while Y.P. was supported by a McDonnell Center for Cellular and Molecular Neuroscience fellowship and C.A. was supported by an R50 Research Specialist Award (1-R50-CA233164-01). The GeiC Center at WUSM engineered the hiPSCs and is subsidized by NCI Cancer Center Support Grant #P30-CA091842.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85084080912&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-15770-3
DO - 10.1038/s41467-020-15770-3
M3 - Article
C2 - 32358581
AN - SCOPUS:85084080912
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2177
ER -