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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Xiaofan Guo & Yuan Pan & Min Xiong & Shilpa Sanapala & Corina Anastasaki & Olivia Cobb & Sonika Dahiya & David H. Gutmann, 2020. "Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15770-3
    DOI: 10.1038/s41467-020-15770-3
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    Cited by:

    1. Corina Anastasaki & Juan Mo & Ji-Kang Chen & Jit Chatterjee & Yuan Pan & Suzanne M. Scheaffer & Olivia Cobb & Michelle Monje & Lu Q. Le & David H. Gutmann, 2022. "Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Jit Chatterjee & Shilpa Sanapala & Olivia Cobb & Alice Bewley & Andrea K. Goldstein & Elizabeth Cordell & Xia Ge & Joel R. Garbow & Michael J. Holtzman & David H. Gutmann, 2021. "Asthma reduces glioma formation by T cell decorin-mediated inhibition of microglia," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

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